The 2 nd Symposium of International
Immunological Memory and Vaccine Forum (IIMVF)

Trends in
Immunological Memory and
Vaccine Development

August 25-26, 2014
La Jolla Institute of Allergy & Immunology
La Jolla, California, U.S.A.

Organized byInternational Immunological Memory and Vaccine Forum
US-Japan Cooperative Medical Sciences Program on Immunology
La Jolla Institute for Allergy & Immunology
Leading Graduate School at Chiba University
Chiba Innovation Program for Therapeutics at Chiba University

The 2nd Symposium of International Immunological Memory and
Vaccine Forum (IIMVF)

Trends in Immunological Memory and
Vaccine Development

August 25-26, 2014
La Jolla Institute of Allergy & Immunology
La Jolla, California, U.S.A.

Welcome Message
We would like to welcome you to the 2nd symposium of “International Immunological
Memory and Vaccine Forum (IIMVF)”.

The 1st symposium was held in Tokyo in

January 2013, in which Drs. Rafi Ahmed, Andreas Radbruch and Stephen Schoenberger,
who are international advisors for our IIMVF gave keynote and special lectures. We
heard about the cutting edge research being conducted in all of our core members’
laboratories. During the meeting, we discussed the outline and the venue of the 2nd
symposium, and Drs. Stephen Schoenberger and Mitchell Kronenberg kindly accepted tohost the 2 nd symposium at LIAI, CA, USA.

The theme of this symposium is “Trends

in Immunological Memory and Vaccine Development”.

About 20 Japanese senior andjunior speakers and 8 US invited and 5 young local speakers will present their recent
work in the symposium.

We have also many poster presentations. More than forty

Japanese scientists and students attend this meeting.

We appreciate all of the advisory

and core members, and the meeting participants of this forum for their active
contribution to the symposium.

We do hope all attendants enjoy presentations,questions and active scientific discussion on immunological memory and vaccine
research.

The aim of the IIMVF is shown below for the purpose of sharing themission and value of the memory and vaccine platform with all of the meeting
participants.

Lastly, we are grateful for the co-organization by the US-JAPANCooperative Medical Sciences Program on Immunology, Leading Graduate School at
Chiba University for help organizing the 2nd IIMVF symposium.
Toshinori Nakayama
Hiroshi Kiyono
Stephen Schoenberger
Mitchell Kronenberg
The organizers of the 2nd IIMVF symposium

1

The Aim of the IIMVF
Currently, more research studies are being undertaken to unlock the mechanisms
underlying antigen-specific immune responses, a characteristic feature of the acquired
immune system that is initiated by the innate immune system.

Although“Immunological Memory” is a central theme in acquired immunity, it is not fully
understood at the molecular, cellular and in vivo levels, and thus this research area
needs to be given further stimulation particularly for the next generation of juniorimmunologists in Japan together with international leading scientists. New idea andfindings from modern research on “Immunological Memory” will contribute to thedevelopment of more effective and safer vaccines against infectious diseases,
therapeutic vaccines for controlling so called pathogenic immune memory cells thattrigger allergy or autoimmune diseases, and vaccines for cancer.

This forum covers

the issues of “immunological memory and vaccine research” in a broad sense, including
basic to clinical immunological studies and translational research for vaccine
development, aiming to provide an interactive and simulative environment for
promoting exchange of new dogma, idea and data among young and establishedimmunologists interesting on the area of immunological memory and vaccine studies
with an international perspective. Hence we launch the International Immunological
Memory and Vaccine Forum (IIMVF) holding a meeting once a year (or as needed) as a
global platform, in order to promote; 1) information exchange and mutual professionaland social friendship among junior researchers, and between junior and seniorresearchers, 2) dissemination of junior researchers’ studies to the world community bymaking presentations and discussions in the presence of world-class research leaders,and 3) industry-academia joint research at the international level, and securement ofresearch funds.
From IIMVF web site “http://www.iimvf.jp/english/history.html”.

2

~Program~
Monday, August 25
9:00

Arrival

9:00-9:10

Welcoming Remarks

Session I

Mucosal immunology (Chair H. Kiyono/K. Takeda)

9:10-9:40

Toshinori Nakayama “Pathogenic Memory Th2 Cells in the
airway”

9:40-9:55

Masaki Miyazaki “Id2 and Id3 maintain the regulatory T cell poolto suppress Th2 inflammatory disease”

9:55-10:25

Mitchell Kronenberg “Mechanisms for the regulation of
mucosal immunity by the herpes virus entry mediator"

10:25-11:00

Coffee Break

11:00-11:30

Kiyoshi Takeda “Regulatory mechanisms of gut homeostasis”

11:30-11:45

Yujun Huang "Driving pre-existing immunity at the mucosal
borders of the intestine”

11:45-12:00

Satoshi Uematsu “Blockade of TLR3 protects mice from lethal
radiation-induced gastrointestinal syndrome”

12:00-1:30

Lunch and Poster Session

Session II

CD4 T cells (Chair: Shane Crotty)

1:30-2:00

Sonoko Habu “The in vitro induction of serial transfer of anergy
status: a model for long lasting immune tolerance”

2:00-2:15

Takanori So “A novel molecular function of TRAF5 in CD4 T celllineage commitment ”

2:15-2:30

Koji Tokoyoda “Resting T helper cell memory in bone marrow”

2:30-3:00

Shane Crotty “Genetics of Tfh differentiation”

3:00-3:15

Norifumi Iijima “A local chemokine network sustains tissueresident memory T cells crucial for antiviral protection”

3:15-3:45

Coffee Break3

Session III

CD8 T cells (Chair: Alex Sette)

3:45-4:15

Alex Sette “Comparative analysis of human T cell
responses to DENV and TB”

4:15-4:30

Makoto Kurachi “The transcription factor BATF operates as
an essential differentiation checkpoint in early effector CD8+
T cells

4:30-4:45

Shiki Takamura “CD69 controls a balance between S1Pand CXCL16-mediated chemotaxis in the establishment of
CD8+ T cell memory in the lung airways”

4:45-5:00

Patrick Metz “Regulation of asymmetric division and CD8+ T
lymphocyte fate specification by PKCζ and PKCλ/ι”

5:00-5:30

Louis Picker “The Unique Immunobiology of Cytomegalovirus
Vectors; New Immunology from a Very Old Virus”

5:30

Adjourn for the day

Tuesday, August 26
Session IV

Vaccines 1 (Chair: Ken Ishii)

9:00-9:30

Hiroshi Kiyono “Mucosal immunity and vaccine development”

9:30-10:00

Bali Pulendran “Systems Vaccinology: enabling rational
vaccine design with systems biology”

10:00-10:30

Ken J Ishii “Innovation and renovation of vaccine adjuvant”

10:30-11:00

Coffee BreakSession V

Novel regulatory pathways (Chair: Erika Pearce)

11:00-11:30

Erika Pearce “Metabolic interactions in the tumor
microenvironment”

11:30-11:45

Wataru Ise “Regulation of germinal center response by thetranscription factor BATF”

11:45 -12:15

Masato Kubo “Notch regulates reciprocal expression of
CCR7 versus CXCR5 to control central memory T cell
generation”

412:15 -12:30

Kiyoshi Hirahara “Asymmetry of STAT action to define
specificity and redundancy of IL-27 and IL-6 signals”

12:30-1:30

Lunch

Session VI

B cells (Chair: Tomohiro Kurosaki)

1:30-2:00

Tomohiro Kurosaki “Mechanisms underlying rapid memory IgG
responses”

2:00-2:30

Daisuke Kitamura “Molecular mechanisms for the developmentof B-cell memory”

2:30-3:00

Nobuo Sakaguchi “Role of GANP in the DNA repair for AIDinduced somatic hypermutation generating high affinity
antibodies”

3:00-3:30

Coffee BreakSession VII

Vaccines 2 (Chair: Hiroshi Kiyono)

3:30-3:45

Klaus Ley “Protective Autoimmunity in Atherosclerosis”

3:45-4:15

Uli von Andrian “A mucosal vaccine against Chlamydia
trachomatis generates two synergistic waves of protective
memory T cells”

4:15-4:30

Raphael Zellweger “Importance of CD8 T cells for protection
against heterotypic Dengue virus infection and antibodymediated severe disease”

4:30-4:45

Sunnie Yoh “PQBP1 is an innate immune receptor for HIV-1”

4:45-5:15

Dennis Burton “HIV vaccine targets identified by broadly
neutralizing antibodies”

5:15-5:30

Closing remarks

5:30-6:45

Refreshments

5

Monday, August 25
Session I
Mucosal Immunology

6

SESSION I

Pathogenic memory Th2 cells in the airway
Toshinori Nakayama, Yusuke Endo, Damon J. Tumes and Kiyoshi Hirahara
Department of Immunology, Graduate School of Medicine, Chiba University, Japan
CREST, Japan Science and Technology Agency, Japan
Immunological memory is a hallmark of adaptive immunity. Memory CD4 T helper(Th) cells are central to acquired immunity, and vaccines for infectious diseases aredeveloped based on this concept. However, memory Th cells also play a critical role in
the pathogenesis of various chronic inflammatory diseases, including asthma. We refer tothese populations as “pathogenic memory Th cells”. I would like to introduce ourexperimental results that address the generation of pathogenic memory Th2 cells in allergic
airway inflammation.
We have found that memory Th2 cells are divided into four subpopulations by
CD62L/CXCR3 expression. All four subpopulations produced IL-4 and IL-13, while only
the CD62LlowCXCR3low population produced IL-5.
Increased levels of H3-K4
methylation at the IL-5 gene locus were specifically observed in this population. Memory
Th2-dependent airway inflammation was attenuated in the absence of the
CD62LlowCXCR3low population. We identified a pathogenic IL-5-producing memory Th2cell subset in allergic airway inflammation (Endo et al. Immunity 35: 733, 2011).
Moreover, we have addressed the mechanisms regulating the pathogenicity of memory Th
cells. Since the expression of the IL-33R;ST2 is high on the pathogenic Th2 cells, weanalyzed whether the IL-33/ST2 axis license memory Th2 cells to induce allergic airway
inflammation via production of IL-5, and an important role for IL-33/ST2 axis was
revealed.
Based on these findings we propose a model named “Pathogenic Th population anddisease induction model” (Fig. 1) wherein a pathogenic subpopulation of Th cells
possessing a distinct feature of effector function (e.g. unique expression of cytokines andchemokine receptors) is generated in vivo and is crucial for the pathogenesis of Th1, Th2 or
Th17 diseases, regardless of the balance of these Th subsets (Endo et al. Trends in
Immunology 35:69, 2014).
Classical Th1/Th2 balancedisease induction model

Allergic disease

Th2

Th1
Th1

Th1
Th1

Th2

＞

Th2

Autoimmune disease(Auto-inflammation)

＞

Fig.1

Naive
CD4 T

Pathogenic Th populationdisease induction model

Th2

Th1
Th1

Allergic disease

Autoimmune disease(Auto-inflammation)

Pathogenic
mTh2

Pathogenic
mTh1

IL-5+
mTh2

Pathogenic
mTh17

IL-17+
mTh1

Th1

IL-23R+

mTh17

Naive
CD4 T

Memory Th cells

Th17

Endo et al. Trends in Immunol. 2014

7

SESSION I

Id2 and Id3 maintain the regulatory T cell pool to suppress Th2
inflammatory disease
Masaki Miyazaki, Cornelis Murre
University of California, San Diego, USA
Regulatory T (Treg) cells suppress the development of inflammatory disease, but ourknowledge of transcriptional regulators that control this function remains incomplete. Here
we show that expression of Id2 and Id3 in Treg cells was required to suppress developmentof fatal Th2 inflammatory disease. We found that T cell receptor (TCR)-driven signaling
initially decreased the abundance of Id3, which led to the expression of CXCR5. Depletionof Id2 and Id3 expression in Treg cells resulted in compromised maintenance andlocalization of the Treg cell population. Transcriptome analysis shows that Id2 and Id3
regulate effector Treg cell transcriptional signitures. Thus, Id2 and Id3 enforce effector Treg
cell checkpoints and control the maintenance and homing of Treg cells. (Nature
Immunology Aug. 2014)

8

SESSION I

Mechanisms for the regulation of mucosal immunity by the herpes virus
entry mediator
Mitchell Kronenberg
La Jolla Institute for Allergy & Immunology, USA
The herpes virus entry mediator (HVEM) is a TNF super family receptor that binds
multiple ligands, including TNF and Ig super family members. We have explored the role of
HVEM in epithelial cells, a radiation resistant cell type critical for preventing chronic
inflammation and enhancing host defense. During Citrobacter rodentium infection by oral
gavage, Hvem-/- mice had impaired colonic epithelial responses, resulting in higher bacterial
burdens, inflammation and increased mortality. HVEM stimulation induced epithelial
responses by a novel signaling pathway, with NIK-dependent Stat3 activation acting
downstream of HVEM, resulting in the expression of genes important for mucosal
immunity. A type of innate lymphoid cells (ILC) called ILC3, also expresses HVEM. ILC3
are characterized by the production of IL-22, and HVEM expression by these cells is
required for their optimal production of this cytokine. In the absence of HVEM
expression by ILC3 in conditional HVEM knockout mice, constitutive IL-22 production is
reduced with corresponding changes in the microbiota and a resulting increase in mucosal
Th17 cells. Therefore, HVEM expression by different cell types in the intestine has
important effects on both innate and adaptive immunity.

9

SESSION I

Regulatory mechanisms of gut homeostasis
Kiyoshi Takeda
Department Microbiology and Immunology, Graduate School of Medicine, WPI Immunology
Frontier Research Center, Osaka University, Japan
Intestine is a unique tissue, where many commensal microbes inhabit. Therefore,
intestinal mucosa is protected from these commensal bacteria as well as pathogenic bacteria
by several types of barriers. One of these barriers is constructed by mucus layers, composedof the inner firm mucus layer and outer loose mucus layer in the large intestine. Commensal
bacteria are present in the outer mucus layer, whereas there is no commensal bacterium in
the inner mucus layer. Separation of commensal bacteria from the intestinal epithelial cells
contributes to prevention of intestinal inflammation. Indeed, the presence of bacteria on theepithelial surface of the large intestine was reported in several mouse models of intestinal
inflammation. However, the precise mechanisms by which the inner mucus layer is free ofbacteria in the large intestine remain unknown.
We found a molecule, which was selectively expressed on the apical surface of theepithelial cells at the top of colonic glands. This molecule was a highly glycosylated
GPI-anchored protein, and cleaved and secreted into the colonic lumen, particularly the
inner mucus layer. In mice lacking this molecule, bacterial free space in the inner mucus
layer disappeared and they were highly susceptible to intestinal inflammation. On theintestinal epithelial cell layer and crypts of the large intestine of the mutant mice, flagellated
bacteria such as Helicobacter spp. and Proteus spp. including P. mirabilis were present.
Depletion of these bacteria by antibiotics restored the bacterial free space in the inner
mucus layer and ameliorated the intestinal inflammation of the mutant mice. This moleculebound to P. mirabilis and inhibited their attachment to the intestinal epithelial cells. Thesefindings demonstrated that this molecule mediates segregation of commensal bacteria fromthe intestinal epithelial layer in the large intestine, and thereby contributes to themaintenance of gut homeostasis.

10

SESSION I

Driving Pre-existing Immunity at the Mucosal Borders of the Intestine
Yujun Huang, Yiran Wang-Zhu, Alexandre Larange, Ryo Shinnakasu, Christopher J. Lena,
Mitchell Kronenberg, and Hilde Cheroutre
La Jolla Institute for Allergy & Immunology, USA
CD8 effector memory T cells (TEM) residing at mucosal epithelium have a heightened
and immediate effector function to prevent invasion of pathogens and to control thesystemic immune sensing. The mechanisms that drive the differentiation of superior tissue
resident TEM are still poorly understood. Previously we have shown that highaffinity/avidity TCR stimulation induces CD8aa expression on the most effective CD8 Teffand that those CD8aahi CD8ab T effector cells (Teff) are selected to become mucosal TEM.
We generated new data showing that the “fittest” CD8aahi CD8+ Teff are favored by strong
TCR stimulation and pro-inflammatory conditions. CD8aa serves as a co-repressor for TCR
signaling and tunes down TCR proximal signaling in order to rescue CD8 Teff from strong
activation-induced cell death (AICD). Strong TCR stimulation and pro-inflammatory
conditions induce more CD8aahi precursor cells and enhance TEM generation in small
intestine. These fully differentiated TEM at the mucosal border have potent protective
immunity against pathogens. Our findings emphasize the importance of tissue resident
TEM for vaccinations and provide important and highly novel insights to design successful
alternative vaccine approaches.

11

SESSION I

Blockade of TLR3 protects mice from lethal radiation-induced
gastrointestinal syndrome
Satoshi Uematsu
Department of Mucosal Immunology, School of Medicine, Chiba University, Japan/
Division of Innate immune regulation, International Research and Development Center for
Mucosal Vaccine, Institute of Medical Science, The University of Tokyo, Japan
High-dose ionizing radiation induces severe DNA damage in the epithelial stem cells insmall intestinal crypts and causes gastrointestinal syndrome (GIS). Although the tumor
suppressor p53 is a primary factor inducing death of crypt cells with DNA damage, its
essential role in maintaining genome stability means inhibiting p53 to prevent GIS is not a
viable strategy. Here, we show that the innate immune receptor Toll-like receptor 3 (TLR3)
is critical for the pathogenesis of GIS. Tlr3-/- mice show substantial resistance to GIS owing
to significantly reduced radiation-induced crypt cell death. Despite showing reduced crypt
cell death, p53-dependent crypt cell death is not impaired in Tlr3-/- mice. p53-dependent
crypt cell death causes leakage of cellular RNA, which induces extensive cell death via
TLR3. An inhibitor of TLR3–RNA binding ameliorates GIS by reducing crypt cell death.
Thus, we propose blocking TLR3 activation as a novel and preferable approach to treat
GIS.

12

NOTE

13

Monday, August 25
Session II
CD4 T Cells

14

SESSION II

The in vitro induction of serial transfer of anergy status: a model for long
lasting immune tolerance.
Naoko Negishi and Sonoko Habu
Department of Immunology, Juntendo University Scholl of Medicine, Japan
Start text here. Immunological memory is greatly important for protecting the individual
against recurring diseases due to similar pathogens, but its cellular and molecular basis is
still not fully understood, particularly the process of generating a particular long-lasting
immunity against pathogens. For challenging this problem, any suitable experimental
system is required. Immune cells responding to recurrent challenge are varied. Amongthem, we are focusing T cells that regulate immune tolerance, particularly transplantation
tolerance where anergy status is maintained for a long duration. To address this issue, wehave recently established the in vitro induction system in which anergy status is seriallytransferred into naïve T cells in turn, using TCR Tg mice in which the TCR recognizes OVA
peptide and also reacts to superantigen TSST-1 through TCR Vb18 chain. In the present
talk, we will introduce the in vitro experimental system we generated and show the featuresof CD4+T cells responsible for serial anergy status. We will also discuss about a possibility
that our established experimental system may be a memory model in which anergy status of
immune system can be generated by serial transfer of certain cell characters.

15

SESSION II

A novel molecular function of TRAF5 in CD4 T cell lineage commitment
Takanori So
Tohoku University Graduate School of Medicine,
Department of Microbiology and Immunology, JapanThe family of 6 TNF receptor-associated factors (TRAFs) function as adaptor proteinsfor the TNF receptor superfamily, the Toll-like receptor family, and the RIG-I-like receptor
family by associating with the intracellular domains of these receptors to mediate
downstream signaling events. Our previous data shows that allergic lung inflammation
mediated by effector CD4 T cells is more exaggerated in Traf5-/- mice than in wild-typemice and suggests that TRAF5 has a function that has not been delineated in detail in CD4
T cells. In this study, we have identified a novel attribute of TRAF5 in IL-6 signaling
pathway. In the presence of IL-6, differentiating naïve Traf5-/- CD4 T cells produced more
IL-17 than did wild-type CD4 T cells and developed a pronounced Th17 phenotype both invitro and in vivo. Accordingly, Th17-associated experimental autoimmune
encephalomyelitis (EAE) was greatly exaggerated in Traf5-/- mice than in wild-type mice,and Traf5-/- CD4 T cells induced exaggerated EAE in TRAF-sufficient recipient mice.
Surprisingly, TRAF5 constitutively associated with gp130 and suppressed the recruitment
and activation of STAT3 in response to IL-6. Amino acid residues 774-798 in thecytoplasmic of gp130 were critical for the binding, and this region contains an SXXE motif
and two di-acidic amino acids, which are recognition elements for the TRAF-C domain.
The finding therefore provides a new perspective on the lineage commitment of CD4 T celldifferentiation and an explanation why TRAF5 exhibits an anti-inflammatory function in
CD4 T cells.

16

SESSION II

Resting T helper cell memory in bone marrow
Koji Tokoyoda
German Rheumatism Research Center Berlin (DRFZ), Germany
Immunological memory provides long-term protective immunity against pathogens
which have encountered before. Memory is maintained by long-lived memory cells,
generated in the primary challenge. Long-lived memory T helper (Th) cells play a crucialrole in the generation, maintenance and reactivation of other memory cells. We havedemonstrated that most of long-lived memory Th cells reside and rest in the bone marrow(BM). In the course of a systemic immune response, CD4 T cells relocate to the BM within
2 months after their generation. Antigen-specific memory Th cells of the BM express Ly-6C
at high level and, upon challenge with antigen, they rapidly express cytokines and CD154
and efficiently induce the production of high-affinity antibodies by B cells. In the BM,
memory Th cells are maintained on IL-7-expressing stromal niches which control theabundance of memory Th cells. However, the molecular mechanisms of their establishment
and maintenance in the BM remained unclear. We have also shown that resting memory Th
cells in the BM express high levels of two activation markers, CD49b and CD69, and thatthe loss of their markers reduces the number of memory Th cells only in the BM. Bothmarkers can work as adhesion molecules for the transmigration of antigen-experienced
CD4 T cells via sinusoids of the bone for the establishment of memory cells. These studies
on these adhesion molecules clarified that BM memory Th cells are generated at a
multi-step process. Here we show the kinetics on localization of memory Th cell precursors
and memory cells during an immune response; memory Th cell precursors transmigrate into
the marrow of bones via Collagen-I+CD144+ sinusoidal endothelial cells, are temporarily
anchored on Collagen-II+ and also CXCL12+ stromal cells, and finally reach on
Collagen-II+ and also Collagen-XI+IL-7+ stromal cells. These results clarify how memory
Th cell precursors relocate to the BM and also help an understanding of how memory cells
are generated temporally and spatially.

17

SESSION II

Genetics of Tfh differentiation
Shane Crotty
La Jolla Institute for Allergy and Immunology, USA
Follicular helper T cells (Tfh) are the specialized providers of T cell help to B cells, andare essential for germinal centers, affinity maturation, and the development of most highaffinity antibodies and memory B cells. Tfh differentiation is a multi-stage, multifactorial
process involving Bcl6 and other transcription factors. Because of their important role
regulating B cells and antibody responses, Tfh appear to be critical components of many
protective immune responses against pathogens, as well as being positively associated withprotective responses against multiple cancers. As such, there is strong interest in harnessing
Tfh cell biology to enhance new vaccines. Tfh cell responses also are major components ofa number of autoimmune diseases associated with autoantibody responses. Overall, there
have been dramatic advances in this young field, but there are still major gaps in our
understanding of Tfh differentiation and functions and there is much to be learned about thebiology of these cells in the interest of applying that knowledge to biomedical needs. Our
recent work has focused on understanding the genetics of Tfh cells. We have used RNAi
based genetic screens and BCL6 Chip-seq to understand Tfh biology. The BCL6 cistrome inprimary human GC TFH cells is markedly distinct from the BCL6 cistrome in primary
human GC B cells. In Tfh, BCL6 directly represses genes regulating T cell migration and
TCR signaling, as well as gene sets defining alternative T cell fates. Although someBCL6 binding sites contained BCL6 binding motifs, BCL6 binding sites were also highly
enriched in AP-1 or STAT motifs. AP-1 complexes are key positive downstream mediatorsof TCR signaling and external stimuli. We show that AP-1 interacts with BCL6 andco-occupies BCL6 binding sites with AP-1 motifs suggesting that BCL6 prevents orsubverts AP-1 activity. The BCL6 cistrome exhibits unique T cell specific features that
may explain how this master regulatory mediates distinct cell-context dependent
phenotypes.

18

SESSION II

A local chemokine network sustains tissue-resident memory T cells crucial
for antiviral protection
Norifumi Iijima and Akiko Iwasaki
Department of Immunobiology, Yale University School of Medicine,USA
Tissue resident memory T cells (T ) are critical in protecting the host from a variety ofpathogens. Some tissues are permissive for T cell entry, while others including the brain,skin and vagina require inducible factors. Skin infection generates CD8 T that aresequestered in the epidermis, and CD4 T cells that traffic rapidly through the dermis into
circulation However, whether CD4 T cells can be established in an otherwise restrictive
tissue, and if so, how such cells are maintained remains unclear. Here, by using parabiotic
mice, we show that a pre-existing pool of memory CD4 T cells in the genital mucosa isrequired for full protection from a lethal herpes simplex virus 2 (HSV-2) infection. The
vaginal memory T cell pool established through local immunization underwent minimal
exchange with the systemic circulation, and was sufficient for protection. In contrast,
circulating memory T cells entered the vagina only after the viral challenge, and provided
only a partial protection against viral replication and disease. Vaginal CD4 T cells weremaintained in distinct memory lymphocyte clusters (MLCs) beneath the epithelial layer
through inducible chemokines secreted by local network of resident cells. Our results
highlight a critical need for vaccine strategies that enable establishment of local memory T
cells for protection from sexually transmitted viruses, and provide insight about how such
pool might be established through a local chemokine network.
RM

RM

RM

RM

19

Monday, August 25
Session III
CD8 T Cells

20

SESSION III

Comparative analysis of human T cell responses to DENV and TB
Alessandro Sette, Cecilia Lindestam, Daniela Weiskopf, Vijay Pandurangan and Bjoern
Peters
La Jolla Institute for Allergy and Immunology, USA
The long-term goal of our research is to characterize immune response profiles that
correlate with the outcome of infection or vaccination. More specifically, our current focus
is on CD4 and CD8 T cell responses associated with two pathogens of widespreadsignificance to human health and disease, namely mycobacteria tuberculosis and dengue
virus. Our approach relies on the evaluation of responses observed 1) in populations
previously exposed and naturally associated with immunity and/or control of infection 2)
individuals associated with active and severe disease
Immune profiling to characterize human3) individuals to which licensed or experimental
adap ve responses in high impact
vaccines have been administered. We will review
pathologies
experiments that led to the identification andNatural immunity
characterization of hundreds of different CD4 and
CD8 T cell epitopes derived from TB and DENV,
and started to define phenotypes associated with
Vaccina on
Ac ve Diseaseprotection, disease and vaccination. In the case of
DENV we will describe phenotypes of protective T
cell responses, as defined by phenotypes in populations from endemic areas, associated withmultiple infections and protection form severe disease. We will present data relating to T
cells restricted by HLA class I and class II molecules associated with decreased or increased
susceptibility to severe disease. These data can be contrasted with those derived from
pathogenic T cell responses, defined by T cell phenotypes observed in longitudinal samplingof PBMCs from DENV infected individuals associated with differential disease severity,from early infection time points into convalescence. Finally, these phenotypes will becompared with those observed following vaccination with experimental DENV
live-attenuated vaccine (DLAV). Likewise, we are also analyzing T cells in the context oftuberculosis infection and vaccination. In this case, we are analyzing T cell responses
associated with a contained TB infection as observed in individuals with latent MTB that areotherwise healthy. These T cell responses are compared to those observed as a result of
exposure to nonpathogenic mycobacteria, and to those induced by BCG vaccination.
2

21

SESSION III

The transcription factor BATF operates as an essential differentiation
checkpoint in early effector CD8+ T cells
Makoto Kurachi1,2,5, R Anthony Barnitz3,5, W Nicholas Haining3,4, E John Wherry1,2
1

Department of Microbiology, University of Pennsylvania Perelman School Medicine, USA
Institute for Immunology, University of Pennsylvania Perelman School Medicine, USA
3
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical
School, USA 4Division of Hematology/Oncology, Children’s Hospital, Harvard Medical
School, Boston, USA 5These authors contributed equally to this work.
2

The transcription factor BATF is required for the differentiation of interleukin 17(IL-17)-producing helper T cells (TH17 cells) and follicular helper T cells (TFH cells).
Herein we identify a fundamental role for BATF in regulating the differentiation of effectorof CD8+ T cells. BATF-deficient CD8+ T cells showed profound defects in effector
population expansion and underwent proliferative and metabolic catastrophe early after
encountering antigen. BATF, together with the transcription factors IRF4 and Jun proteins,bound to and promoted early expression of genes encoding lineage-specifictranscription-factors (T-bet and Blimp-1) and cytokine receptors while paradoxically
repressing genes encoding effector molecules (IFN-g and granzyme B). Thus, BATF
amplifies T cell antigen receptor (TCR)-dependent expression of transcription factors andaugments the propagation of inflammatory signals but restrains the expression of genes
encoding effector molecules. This checkpoint prevents irreversible commitment to aneffector fate until a critical threshold of downstream transcriptional activity has beenachieved.

22

SESSION III

CD69 controls a balance between S1P- and CXCL16-mediatedchemotaxis in the establishment of CD8+ T cell memory in the lungairways
Shiki Takamura
Department of Immunology, Kindai University Faculty of Medicine, Japan
Memory CD8+ T cells persist in the lung airways of both humans and animals following
resolution of a respiratory virus infection and play a key role in mediating the initial phaseof the recall response to secondary infection. These cells are separated from the circulationand thus categorized as a tissue-resident memory (TRM) population. Unlike CD8+ TRM cells
that reside in the other sites, the number of CD8+ TRM cells in lung airway is maintained bya process of continual recruitment. However, the mechanisms by which these cells arerecruited to the lung airways during steady-state conditions are poorly understood. We showthat reactivation of memory CD8+ T cells in the lung parenchyma is vital for the conversion
form TEM to TRM and subsequent recruitment to the lung airways. Upon reactivation,
memory CD8+ T cells upregulate two key molecules, CD69 and chemokine receptor
CXCR6. CD69 inhibits sphingosine-1-phosphate receptor 1(S1P1)-mediated egression ofmemory CD8+ T cells from the lung parenchyma, while CXCR6 promotes migration
toward CXCL16 expressed in the lung airways. Thus, CD69 and CXCR6 cooperatively
promote the recruitment of memory CD8+ T cells to the lung airways. Our findings thatreactivation in the lung parenchyma is required for continual recruitment of memory CD8+
T cells to the lung airways has important implications for the development of vaccines that
promote durable and effective immunity against respiratory pathogens, such as influenza
virus.

23

SESSION III

Regulation of Asymmetric Division and CD8+ T Lymphocyte Fate
Specification by PKCζ and PKCλ/ι”
Patrick Metz, Janilyn Arsenio, Boyko Kakaradov, Stephanie H. Kim, Kelly Remedios,
Katherine Oakley, Gene W. Yeo, John T. Chang
UCSD, USA
During an immune response against a microbial pathogen, naïve T lymphocytes give riseto effector cells that provide acute host defense and memory cells that provide long-lived
immunity. It has been shown that activated naïve T lymphocytes can undergo asymmetric
division, enabling the daughter cells to inherit unequal amounts of fate-determining proteins
and thereby acquire distinct fates from their inception. Here, we show that the absence of
the atypical protein kinase C (aPKC) isoforms, PKCζ and PKCλ/ι, disrupts asymmetricCD8+ T lymphocyte division, resulting in aberrant acquisition of a ‘pre-effector’transcriptional program, detected by single-cell gene expression analyses, in lymphocytesthat had undergone their first division in vivo. These alterations were associated withenhanced differentiation toward effector fates at the expense of memory fates. Together,
these results demonstrate a role for aPKC in regulating asymmetric division and thespecification of divergent CD8+ T lymphocyte fates early during an immune response.

24

NOTE

25

Tuesday, August 26
Session IV
Vaccines 1

26

SESSION IV

Mucosal Immunity and Vaccine Development
Hiroshi Kiyono
Division of Mucosal Immunology, Department of Microbiology and Immunology,
International Research and Development Center for Mucosal Vaccines,
The Institute of Medical Science, The University of Tokyo, JapanThe epithelium of digestive tract is continuously exposed to infinite beneficial andharmful antigens including commensal and pathogenic microbe, in handling its day-to-day
duties. The digestive tract is thus equipped with the mucosal immune system (MIS) offering
the first line of defense against invasion of pathogens at same time, the MIS also creating ahomeostatic condition to commensal microorganisms. Fucosylation of intestinal epithelial
cells, catalyzed by fucosyltransferase 2 (Fut2), is a major glycosylation mechanism of host–microbiota symbiosis. Our most recent study has shown that innate lymphoid cells (ILCs)
induced intestinal epithelial Fut2 expression and fucosylation. Deficiency of intestinal
ILC-mediated fucosylation led to increased susceptibility to infection by Salmonella
typhimurium. Further, these ILCs play a critical role in the creation of intra-tissue
co-habitation of commensal flora, Alcaligenes in Peyer’s patches. Our data reveal criticalroles of ILCs in shaping the gut microenvironment through the regulation of epithelial
glycosylation and containment of intra-tissue commensal flora.
Gut pathogen-induced diarrhea is a life-threatening disease in developing countries.
Based on our knowledge in mucosal immunology and cross fertilization with agriculturescience, our effort has been aiming to develop rice transgenic (Tg) vaccine system,“MucoRice”. Tg rice expressing B subunit of cholera toxin (MucoRice-CTB) has beenshown to induce antigen-specific SIgA-mediated protective immunity against Vibrio
cholera-induced diarrhea. Our study has been extended to construct Tg rice expressing theneutralizing variable domain of a rotavirus-specific nanoantibody. Orally administered
MucoRice-ARP1 markedly decreased the viral load in rotavirus-challenged mice. The
MucoRice system is thus an attractive vaccine antigen and nanoantibody expression,preservation and delivery platform for the development of next generation of mucosal
vaccines.
1.
2.
3.
4.
5.

Goto, Y., et al. 2014. Innate lymphoid cells regulate intestinal epithelial cell
glycosylation. Science (in press)
Sonnenberg, G.F., et al. 2012. Innate lymphoid cells promote anatomical containmentof lymphoid-resident commensal bacteria. Science 336:1321-1325.
Goto, Y., et al. 2012. Epithelial barrier: An interface for the cross-communication
between gut flora and immune system. Immunol Rev. 245:147-163.
Tokuhara, D., et al. 2013. Rice-based oral antibody fragment prophylaxis and therapy
against rotavirus infection. J. Clin. Invest. 123:3829-3838.
Tokuhara, D., et al. 2010. Secretory IgA-mediated protection against V. cholerae andheat-labile enterotoxin-producing enterotoxigenic Escherichia coli by rice-based
vaccine. Proc. Natl. Acad. Sci. USA. 107: 8794-8799.
27

SESSION IV

Systems Vaccinology: enabling rational vaccine design with systems
biologyBali Pulendran
Emory Vaccine Center, Emory University, USA
Despite their great success, we understand little about how effective vaccines stimulate
protective immune responses. Two recent developments promise to yield such
understanding: the appreciation of the crucial role of the innate immune system in sensing
microorganisms and tuning immune responses, and advances in systems biology. In thispresentation, I will discuss how these developments are yielding insights into themechanism of some of the most successful vaccines ever developed. Furthermore, suchdevelopments promise to address a major challenge in vaccinology: that the efficacy of a
vaccine can only be ascertained retrospectively, upon infection. The identification ofmolecular signatures induced rapidly after vaccination, which correlate with and predict thelater development of protective immune responses, would represent a strategy toprospectively determine vaccine efficacy. Such a strategy would be particularly useful whenevaluating the efficacy or immunogenicity of untested vaccines, or in identifying
individuals with sub-optimal responses amongst high risk populations, such as infants orthe elderly. We have recently used a systems biology approach to identify early genesignatures that correlate with, and predict the later immune responses in humans vaccinatedwith the live attenuated yellow fever vaccine YF-17D, or with the influenza vaccines. I will
review these studies, and discuss their broader implications for vaccinology.

28

SESSION IV

Innovation and renovation of vaccine adjuvant
Ken J Ishii1,2
1. Laboratory of Adjuvant Innovation, National Institute of Biomedical Innovation (NIBIO),
Japan
2. Laboratory of Vaccine Science, Immunology Frontier Research Center (IFREC), Osaka
University, JapanThe word adjuvant has its origin from the Latin "adjuvare", meaning "to help". It is a
general term for substances (factors) which are co-administered with a vaccine with the aimof increasing the effect (immunogenicity) of the vaccine. The research and development ofadjuvants has a history of more than 80 years, and their actual mechanism was not
immunologically understood for a long time, with a famous sarcastic remark"Immunologist's dirty little secret". Recent advance in Immunolgy; however, allowed thedevelopment of adjuvants through an innovative scientific approach, and there is fierce
competition worldwide for the development of next-generation adjuvants. I would like tointroduce and discuss about several adjuvants with their novel mechanisms, including asmall compound as a potent DAMPs inducer to target certain innate immune mechanisms.
On the other hand, however, adjuvants range widely in terms of origin and mode ofaction, and they may be the cause or underlying cause of vaccine toxicity, especiallyimmunotoxicity. I will present our recent work that common particulate adjuvants can cause
local but sustained inflammation and allergic responses via novel innate immune
mechanisms and cell death.
1: Kobiyama K et al Nonagonistic Dectin-1 ligand transforms CpG into a multitask nanoparticulate
TLR9 agonist. Proc Natl Acad Sci U S A. 2014 111(8):3086-91.
2: Kuroda E, Coban C, Ishii KJ. Particulate adjuvant and innate immunity: past achievements,
present findings, and future prospects. Int Rev Immunol. 2013 32(2):209-20.
3: Jounai N, et al. Recognition of damage-associated molecular patterns related to nucleic acids
during inflammation and vaccination. Front Cell Infect Microbiol. 2012;2:168.
4: Desmet CJ, Ishii KJ. Nucleic acid sensing at the interface between innate and adaptive immunity
in vaccination. Nat Rev Immunol. 2012 12(7):479-91.
5: Marichal T et al. DNA released from dying host cells mediates aluminum adjuvant activity. Nat
Med. 2011 17(8):996-1002.

29

Tuesday, August 26
Session V
Novel Regulatory Pathways

30

SESSION V

Metabolic interactions in the tumor microenvironment
Erika L. Pearce, Jing Qiu, Chih-Hao Chang
Department of Pathology & Immunology, Washington University School of Medicine, USA
Metabolism is the set of biochemical reactions that occur within cells to sustain life. As
such, metabolism, by definition, remains the single most fundamental force driving cellfate. Given the critical nature of T cells in clearing and controlling infections and cancer, as
well as mediating protective immunity over the long-term, it is logical that a considerable
effort is made to target these cells for therapeutic purposes. However, while metabolism
regulates the fate and function of T cells, or of any immune cell for that matter, metabolic
interventions for manipulating immunity are rare and can be considered a largely untapped
opportunity. Our research is focused on establishing fundamental mechanisms of metabolic
regulation in T cells, with a view toward identifying new ways to regulate immune cellfunction through the manipulation of metabolic pathways. Underlying mechanisms of how
T cell metabolism and function is altered in the tumor microenvironment will be discussed.

31

SESSION V

Regulation of germinal center response by the transcription factor BATF
Wataru Ise1 and Tomohiro Kurosaki1,2
1

Laboratory of Lymphocyte Differentiation, WPI Immunology Frontier Research Center,
Osaka University, Japan, 2Laboratory for Lymphocyte Differentiation, RIKEN Center for
Integrative Medical Sciences, Japan
In response to T cell-dependent antigens, antigen-specific B cells interact with follicularhelper T cells and are driven into the germinal center (GC) reaction, which is critical for thegeneration and selection of memory B cells and plasma cells that express somaticallymutated high-affinity antibodies. The transcription factor BATF is essential for theformation of follicular helper T cells and thus GC, although whether BATF plays a distinctrole in GC B cell remains unclear. To elucidate B-cell intrinsic function of BATF in vivo,
we generated Batf floxed mice, which allowed us tissue-specific or inducible deletion of
Batf and examined the effect of Batf deficiency in B cells on the induction or maintenanceof GC response.
We found that GC formation was completely absent in mice in which Batf was deleted in
B cells, after immunization with protein Ags. This effect was evident as early as day 5-7
following immunization, suggesting that BATF regulates early GC programs. Furthermore,
GC response was collapsed when Batf was inducibly deleted from mature GC B cells afterday 10-14 following immunization, suggesting that BATF might control sustained GC B
cell proliferation. Thus, our results demonstrate a B-cell intrinsic requirement for BATF for
not only generation but also for maintenance of GC formation.

32

SESSION V

Notch regulates reciprocal expression of CCR7 versus CXCR5 to control
central memory T cell generation
Masato Kubo1,2, Yohsuke Harada1
1

Division of Molecular Pathology, Research Institute for Biomedical Science, Tokyo
University of Science, Japan
2
Laboratory for Cytokine Regulation, RCAI, RIKEN Center for Integrative Medical
Sciences (IMS), RIKEN Yokohama Institute , Japan
Notch signaling is currently reported to control the TFH cell program by modification of
the balance between Bcl6 and Blimp1 expression (J Immunol 2013; 191:2344-2350), andthese TFH cells seems to have a greater propensity to be maintained as memory T (TM)cells. Here we found that TFH cells lacking Notch signaling in Rbpjf/f cd4-cre mice failed togenerate TM cells and recall response in three different antigen systems, influenza virus
infection, OVA-specific OTII Tg system, and a pMHCII tetramer-based system. Adaptive
transfer of OVA-specific TFH cell revealed that TM cells is considered to be maintained in
specialized niches as central memory (TCM) cells in the T cell zone near the T-B borderarea. TFH lost the expression of CCR7, and at 7 days after transfer, TFH cells re-expressed
CCR7 in transcription and protein level, instead of down-regulation of CXCR5 expression,
subsequently leading to localization of memory niches. However, the TFH cells derived
from Rbpjf/f cd4-cre mice exhibited abnormal migration as a consequence of defect of
CCR7 up-regulation. Importance of the CCR7 up-regulation responsible for TCM
re-localization was confirmed by the functional evidence that the CCR7 blockade by
antibody administration in normal mice terminated memory response. Moreover,Tamoxifen based conditional deletion of Rbpj indicated that input of Notch signaling was
required at initial priming, but the deletion in contraction phase did not affect memory
function. The defect of CCR7 up-regulation observed in Rbpj deficiency was due to theenhanced expression of prdm1 (Blimp1), suggesting that the Notch-regulated Blimp
expression had a role in the negative regulation of CCR7 expression. These data
demonstrate that the Notch signaling have a great impact on memory maintenance regulatedby the CCR7 up-regulation as a result of unbalanced regulation of Blimp1 and Bcl6.

33

SESSION V

Asymmetry of STAT action to define specificity and redundancy of IL-27
and IL-6 signals
Hiyoshi Hirahara1,2, Yuka Kanno2, Toshinori Nakayama3,4, John J O’Shea2
1

Department of Advanced Allergology of the Airway, Graduate School of Medicine, Chiba
University, Japan2
Molecular Immunology and Inflammation Branch NIAMS, National Institutes of Health,USA
3
Department of Immunology, Graduate School of Medicine, Chiba University, Japan.
4Japan Science and Technology Agency, Core Research for Evolutional Science andTechnology, Japan
Interleukin (IL-)6 and IL-27 are regarded as pro-inflammatory and anti-inflammatory
cytokines, respectively. While both cytokine-signals go through gp130 and use STAT3 andSTAT1 as signal transducing factors. In order to understand how specificity and redundancyof cytokine action is formulated, we conducted genome-wide transcriptome and chromatin
mapping analysis in T helper cells. The loss of STAT3 significantly collapsed the size oftranscriptional output regulated by IL-6 or IL-27, while the loss of STAT1 reduced diversity
between IL-6 and IL-27 regulated genes. STAT1 gain-of-function mutations in human led toenhanced diversity between IL-6 and IL-27. On key genes that define T helper phenotype,gene expression was fine-tuned by balancing act of STAT3 and STAT1 on chromatin. Thus,
the results indicated that STAT3 is a fundamental driver for both IL-6 and IL-27 response
whereas STAT1 is an important modulator to shape cytokine unique signature, particularlyof IL-27.

34

NOTE

35

Tuesday, August 26
Session VI
B Cells

36

SESSION VI

Mechanisms underlying rapid memory IgG responses
Tomohiro Kurosaki1,2, Kohei Kometani2, Wataru Ise1
1. WPI Immunology Frontier Research Center, Osaka University, Japan
2. RIKEN Center for Integrative Medical Sciences, JapanOne striking feature of humoral memory response is quick generation of neutralizing
antibodies (Abs) upon re-invasion of pathogenic micro-organisms and eliminating themfrom our body. However, it is still unclear about cellular and molecular mechanisms
underlying such quick humoral responses.
By using model T-dependent antigens, we propose that the following three mechanisms
synergistically operate. First, IgG type memory B cells are pre-localized in the place where
they can gain easy access to the antigen. Second, Tfh type memory T cells, which residenear to the memory IgG B cells. These memory T cells are promptly activated byantigen-presentation on IgG memory B cells and re-express Bcl6, which in turn activates
IgG memory B cells. Finally, IgG memory B cells undergo repression of the Bach2transcription factor (one of the BCR-extrinsic changes) during primary immune responses,
which in turn, contributes to rapid differentiation towards plasma cells.

37

SESSION VI

Molecular mechanisms for the development of B-cell memory
Kei Haniuda, Saori Fukao, Tadahiro Kodama, Hitoshi Hasegawa, Daisuke Kitamura*Research Institute for Biomedical Sciences, Tokyo University of Science, Japan
During T-dependent (TD) immune response, antigen-bound B cells undergo
class-switching from IgM to IgG, and proliferate extensively to form germinal centers (GC)in the secondary lymphoid organs. After accumulating mutations at Ig V region genes, GC
B cells with high antigen-binding affinity are selected and differentiate into either
long-lived plasma cells (LLPCs) or memory B (Bmem) cells. Although this phenomenon iswell known, mechanisms for the development and maintenance of Bmem cells remain poorly
understood. Recently, it has been shown that B cells also switch to IgE in the GC but the
IgE+ B cells immediately become short-lived plasma cells and not differentiate into LLPCsor Bmem cells in healthy individuals. Thus, unlike IgG classes, serum IgE emerges onlytransiently at the early phase of the immune response and normally maintained at very low
level, and IgE+ Bmem cells can hardly be detected even after TD immunization, thus
preventing the onset of allergic disorders. To study how the IgE+ Bmem cell development isregulated will help us to understand the mechanism of IgG+ Bmem cell development.
To study the regulatory mechanisms of IgE+ B cell development, we utilized in-vitro
induced germinal center-like B (iGB) cells. The iGB cells cultured on a feeder layer
expressing CD40L and BAFF with IL-4 proliferate extensively while switching either to
IgG1 or IgE. When transferred into mice, IgG+ iGB cells generate memory-like B cells thatsurvive for more than 2 months in the recipient, whereas IgE+ iGB cells transiently become
plasma cells and shortly disappear. Using iGB cells from “floxed” V-gene knock-in micecarrying Cγ1-cre transgene, we swapped the endogenous Ig H chain with exogenous onesof a given class. With this system, we found that IgE-class B-cell receptor (BCR)
constitutively recruited BLNK and CD19-PI3K, resulting in IRF4-Blimp1 induction andspontaneous plasma cell differentiation. Crosslinking of IgE-BCR induced more robust andsustained tyrosine phosphorylation of cellular proteins including BLNK than that of IgG1.
BLNK inhibited endocytosis of antigen-bound IgE-BCR and sustained activation ofdownstream signaling, resulting in attenuation of antigen presentation by IgE+ B cells. In
the BLNK-deficient mice, IgE+ GC B and Bmem cells remained high in number during the
TD response, and more IgE+ LLPCs were produced, rendering the mice hypersensitive tothe secondary challenge. These results together suggest that BLNK regulates both antigen
independent and dependent IgE signaling, facilitating IgE+ B cells to differentiate into
short-lived plasma cells, and prohibiting their clonal expansion in the GCs anddifferentiation into Bmem cells or LLPCs. Considering the IgG+ Bmem cell development, yet
unknown signaling properties of IgG-BCR, especially in terms of BLNK-involvement, may
affect the memory fate determination in the immune response.

38

SESSION VI

Role of GANP in the DNA repair for AID-induced somatic hypermutation
generating high affinity antibodies
Nobuo Sakaguchi, Mohammed Mansour Abbas Eid, Shailendra Kumar Singh, Sarah
Ameen Almofty, Mayuko Shimoda, and Kazuhiko Maeda
Department of Immunology, Graduate School of Medical Sciences, Kumamoto University,
Japan
Antigen (Ag) stimulation induces affinity maturation of BCRs during proliferation of
Ag-specific B-cells in germinal centers (GCs) of peripheral lymphoid organs.
Activation-induced cytidine deaminase (AID) is inevitable for induction of somatic
hypermutation (SHM) at immunoglobulin variable region (IgV-region) genes. The
Neuberger’s original and the later modified models demonstrate that AID-induced C
deamination primarily converts to U generating transition mutations of C→T and G→A.
Uracil DNA Glycosylase (UNG) mounts further diversification at the U position to generate
the transversion of C→A and G→T mutations. The UNG bares the DNA positions to giverise abasic sites, rendering the DNA strands sensitive to endonucleases and the physicalstresses causing the breaks to either single strand or double strands DNA. These are
eventually thought to repair through various DNA repair pathways including the baseexcision repair or the short patch repair mechanisms, all of which are expected to increase
the SHM frequency of the IgV-region. However, it is unclear if only the increase of
IgV-region SHM is necessary for affinity maturation.
Our current approach studied the molecular mechanism how such DNA injuries arecontrolled during the generation of SHM at the IgV-region genes in B-cells. To generate
IgV-region SHM, AID needs to be accompanied with a co-factor for recruitment from thecytoplasm to the nucleus and toward the IgV-region nucleosomes in B-cells. Germinal
center-associated nuclear protein (GANP) helps and enhances the AID accessibility throughdirect interaction at the cytoplasm and loosening the IgV-region nucleosomes by the
GANP’s acetyl-transferase (HAT) activity.
Here, we demonstrate that GANP plays a critical role in the quality control of SHM
profile at the IgV-region genes in B-cells through regulating the choice of DNA repair
pathways favoring the less harmful and high integrity condition. Furthermore, GANP
regulates the amino acid change profile to maintain the overall protein structure of highaffinity antibodies against the immunized Ag. This notion would be important for
generating high affinity BCRs of Ag-reactive B-cell clones and maintaining memory B-cellcondition in the acquired immunity.

39

Tuesday, August 26
Session VII
Vaccines 2

40

SESSION VII

Protective Autoimmunity in Atherosclerosis
Klaus Ley, Kevin Tse, Takayuki Kimura, John Sidney, Alex Sette
LIAI, USA
Immunization of atherosclerosis-prone mice with low density lipoprotein (LDL) or its
oxidized derivative (ox-LDL) was previously shown to be atheroprotective, but neither theantigen specificity nor the mechanism of protection is known. T-helper 1 CD4 T cells (Th1)
are pro-atherogenic and regulatory CD4 T cells (Tregs) are atheroprotective in adoptive
transfer mouse models. In two immunization studies, we tested the ability of five peptides
from mouse Apo B, the main apolipoprotein in LDL, in a 1xCFA + 4xIFA (complete andincomplete Freund’s adjuvant) to prevent atherosclerosis in Apoe-/- mice, a widely usedmodel of atherosclerosis. The five peptides were selected for binding to mouse MHC-II(I-Ab, apparent binding affinities between 4.3 and 95 nM). Vaccination with each of thefive peptides, but not irrelevant control peptides, reduced aortic en face lesion size by
35-60%, accompanied by small but significant atheroprotection in the aortic root. We saw
no change in the number of FoxP3+CD25+ Tregs in lymph nodes or spleens, but
significantly increased expression of IL-10 mRNA induced in aortas of immunized mice.
The number of CD11c+CD103+RALDH+ dendritic cells (DCs), a phenotype that is
consistent with DCs inducing peripheral tolerance, was expanded in aortas of immunized
mice. B1a cells, a cell type thought to secrete atheroprotective antibodies, were expanded in
the peritoneal cavities of immunized mice. We conclude that vaccination with MHC-II
restricted peptides can protect from atherosclerosis in a relevant mouse model. Efforts areunder way to generate MHC-II-peptide tetramers to detect antigen-specific T cells andidentify their phenotype, to identify the nature of the IL-10 producing cells, and to translate
this mouse work to develop an atheroprotective vaccine for humans.

41

SESSION VII

A mucosal vaccine against Chlamydia trachomatis generates two
synergistic waves of protective memory T cells
Georg Stary1, Andrew Olive1, Aleksandar F. Radovic-Moreno2, 3, David Gondek1, David
Alvarez1, Pamela A. Basto2, 3, Mario Perro1, Vladimir D. Vrbanac4, Andrew M. Tager4,
Jeremy A. Yethon5, Omid C. Farokhzad6, Robert S. Langer3, Michael N. Starnbach1 andUlrich H. von Andrian1
1) Division of Immunology, Department of Microbiology and Immunobiology, Harvard
Medical School, USA 2) Harvard-MIT Division of Health Sciences & Technology,
Cambridge, USA 3) Department of Chemical Engineering, Massachusetts Institute ofTechnology, Cambridge, USA 4) The Center for Immunology and Inflammatory Diseases,
Massachusetts General Hospital, Harvard Medical School, USA 5) Sanofi Pasteur, USA
6) Laboratory of Nanomedicine and Biomaterials, Department of Anesthesiology, Brigham& Women’s Hospital, Harvard Medical School, USA
Vaccines that are administered via non-mucosal routes are often poorly protective against
mucosal pathogens, presumably because such vaccines do not generate memory cells that
migrate to mucosal surfaces. Although mucosa-tropic memory cells are inducible bymucosal immunization, few mucosal vaccines are currently in clinical use because live
vaccine vectors pose safety risks and killed pathogens or molecular antigens (Ags) are weak
immunogens when applied to intact mucosa. This poor immunogenicity can potentially beovercome by adjuvants, however, most conventional mucosal adjuvants possess
unfavorable safety profiles. Moreover, the immune mechanisms of protection against manymucosal infections are not well understood. One case in point is Chlamydia trachomatis(Ct), a sexually transmitted intracellular pathogen that can cause mucosal infections
resulting in female infertility and ectopic pregnancies, as well as blindness in thedeveloping world and pneumonia in infants. In mice, genital Ct infection induces protective
immunity that is thought to depend on interferon- (IFN-) producing CD4 T cells. By
contrast, we observed that mucosal exposure to UV-inactivated Ct (UV-Ct) generates
tolerogenic Ct-specific regulatory T cells, resulting in exacerbated bacterial burden upon
subsequent Ct infection. Here, we show that mucosal immunization with UV-Ct complexedwith charge-switching synthetic adjuvant particles (cSAP) did not exert the tolerogenic
effect of UV-Ct alone but elicited long-lived protection against genital Ct infection. Thisdifferential effect of UV-Ct-cSAP versus UV-Ct was because the former was preferentiallypresented by immunogenic CD11b+CD103– dendritic cells (DCs), while the latter was
primarily acquired by tolerogenic CD11b–CD103+ DCs. Notably, genital protection wasachieved after either intrauterine (i.u.) or intranasal (i.n.), but not subcutaneous (s.c.)immunization with UV-Ct-cSAP and was inducible in conventional and humanized mice
alike. Regardless of vaccination route, UV-Ct-cSAP induced robust circulating and splenic
Ct-specific IFN-+ memory CD4 cells. However, only mucosal vaccination, like mucosal
infection with live Ct, induced an early wave of Ct-specific CD4 memory cells that
established long-term residence in the genital mucosa. Antibody inhibition experiments andstudies in parabiotic mice showed that in the absence of early mucosal seeding by
tissue-resident memory cells, mice were poorly protected against Ct, even when circulating
memory cells were abundant. However, for optimal clearance of Ct, a second memory cellwave needed to be recruited to the infected tissue from the circulating pool. Thus, using anovel platform for mucosal immunization, we demonstrate that protection against Ct
depends on the synergistic action of two discrete memory T cell subsets with distinct
differentiation kinetics and migratory properties.
42

SESSION VII

Importance of CD8 T cells for protection against heterotypic dengue virus
infection and antibody-mediated severe dengue disease
Raphael Zellweger, William Eddy, William Tang, Sujan Shresta
LJI, USAThe four serotypes of dengue virus cause pathologies ranging from the febrile illness
dengue fever to the potentially lethal severe dengue disease. A major risk factor for
developing severe disease is the presence of sub-neutralizing levels of antibody from aprevious infection, or, in the case of infants, from a dengue-immune mother. Despite therisk of antibody-mediated severe dengue disease, the goal of dengue vaccine development
efforts has been to induce a neutralizing antibody response against the four dengue
serotypes. To date, no vaccine has been licensed, and Phase IIb and III results of the mostadvanced dengue vaccine candidate in development showed an overall efficacy of only
30% and 57%, respectively. We investigated the role of CD8 T cells in protection against
dengue virus infection using mouse models. We demonstrate that CD8 T cells induced by
one serotype are protective not only against that serotype (homotypic protection), but also
mediate cross-protection against the other serotypes (heterotypic protection). Moreover, weshow that an efficient CD8 T cell response can prevent antibody-induced severe dengue
disease. Our data imply that a vaccine strategy that induces efficient CD8 T cell responses
reduce the risk of antibody-mediated severe dengue disease and increase protection acrossall serotypes. Therefore, a vaccine that triggers both arms of the immune system may beboth safer and more efficient than those that focus on humoral responses alone.

43

SESSION VII

PQBP1 is an Innate Immune Receptor for HIV-1
Sunnie Yoh, Monika Schneider, Stephen Soonthornvacharin, Rana E. Akleh, Kevin C.
Olivieri, Paul De Jesus, Chunhai Ruan, Elisa de Castro, Pedro A. Ruiz, Adolfo
Garcia-Sastre, Sumit K. Chanda

Innate immune responses that trigger type-I interferon (IFN) secretion have been
implicated in HIV-1 transmission and pathogenesis. HIV-1 has evolved countermeasures toescape the activities of several IFN-stimulated genes (ISGs), and those mechanisms notdisabled by the virus define both cell type and species tropisms. Recent data suggest that
one or more intrinsic signaling pathways sense invariant features encoded by HIV-1 andinitiate innate immune responses, including IFN secretion. This response is proximallymediated by recognition of specific viral components in infected cells by patternrecognition receptors (PRR), resulting in the activation of transcription factors thatparticipate in ISG expression and IFN synthesis, such as IRF3. Dendritic cells (DCs) play a
critical role in the immune response to viral infection through the facilitation of cell
intrinsic antiviral activity and the activation of adaptive immunity. Productive infection of
DCs by HIV-1 triggers an IRF3-dependent innate immune response, which has recently
been shown to require the activity of cyclic GAMP synthase (cGAS). Here, we report theresults of a targeted RNAi screen utilizing primary human monocyte-derived DCs(MDDCs) to identify cellular immune regulators that directly interface with HIV-1-encodedfeatures to initiate this innate response. One of the strongest candidates that emerged fromthis screen was polyglutamine binding protein 1 (PQBP1). We found that PQBP1 isrequired for IRF3-dependent signaling in HIV-1-infected MDDCs and human cell lines.
PQBP1 directly binds to reverse-transcribed HIV-1 DNA and interacts with cGAS toinitiate an IRF3-dependent innate response in myeloid cells. Our results demonstrate thatPQBP1 acts as a proximal sensor of a pathogen-associated molecular pattern (PAMP)
encoded by HIV-1 DNA to activate cGAS/IRF3-dependent antiviral responses.

44

SESSION VII

HIV vaccine targets identified by broadly neutralizing antibodies
Dennis R Burton
Dept of Immunology and Microbial Science, Center for HIV/AIDS Vaccine Immunology and
Immunogen Discovery, and IAVI Neutralizing Antibody Center, The Scripps ResearchInstitute, USA
Ragon Institute of MGH, MIT and Harvard, USA
Highly antigenically variable viruses such as HIV present huge problems for vaccine
design. Broadly neutralizing antibodies to HIV generated during natural infection canidentify weaknesses in the surface structures of the virus. These weaknesses can help guidevaccine and drug design and reveal fascinating aspects of the interplay between two highly
mutable systems-the virus and antibody.

45

Poster Session

46

POSTER SESSION

Notch signaling promotes Tfh memory cell generation by facilitating
migration into survival niche
Yohsuke Harada1, Koji Tokoyoda2, Kousuke Miyauchi3, Yasuyo Harada1, Asami
Hanazawa2, Osamu Ohara4, Masato Kubo1,3
1

Research Institute for Biomedical Science, Tokyo University of Science, Japan
German Rheumatism Research Centre (DRFZ), Germany
3
Laboratory for cytokine regulation, 4Laboratory for Integrative Genomics, RCAI, RIKEN
Center for Integrative Medical Sciences (IMS-RCAI), Japan2

T follicular helper (Tfh) cells in germinal centers (GCs) facilitate antibody responses bysecreted cytokines and direct interactions with B cells. It has been suggested that memory
Tfh cells are generated and contribute to a secondary humoral response. Thus, to clarify themechanisms for generation of memory Tfh cells is relevant for effective vaccine design.
Here we demonstrate that Notch signaling regulates generation of memory Tfh cells.
During contraction phase, up-regulation of CCR7 and down-regulation of CXCR5 brings
Tfh cells into the T-B border area, where they are maintained as central memory (TCM)
cells. Lack of Notch signaling during initial antigen priming, but not at the contraction
phase, led to a failure of memory T cell generation due to abnormal migration caused by
defective CCR7 up-regulation. Notch signaling regulated CCR7 expression throughsuppression of Prdm1 (Blimp-1) expression. Our findings indicate that Notch signaling is
critical for the generation and function of TCM cells and could be a future target for thevaccination strategy.

47

POSTER SESSIONGANP-mediated APOBEC3G targeting in generation of non-infectious
HIV-1viruses
Kazuhiko Maeda, Sarah Ameen Almofty, Mayuko Shimoda, Shailendra Kumar Singh,
Mohammed Mansour Abbas Eid, and Nobuo Sakaguchi
Department of Immunology, Graduate School of Medical Sciences, Kumamoto University,
Japan
GANP was designated as a mammalian homologue of the yeast prototype component oftranscription/export-2 complex that is essential for mRNA export, implicating its
potentiality in transcription and RNA metabolism. GANP is associated with cytidine
deaminase AID and involved in AID-targeting toward the rearranged IgV-region gene for
Ab-affinity maturation in B cells. Here, we demonstrate that GANP is upregulated in
activated CD4+ T cells and interacted with APOBEC3G (A3G) protein, another member of
AID/APOBEC family. Upon HIV-1 infection, GANP augments targeting of A3G toward
HIV-1 genomic RNA in the cores of secreted virions. This enhances mutation at A:T pairsof the reverse transcribed HIV-1 genomic cDNA, producing non-infectious HIV-1 virus
particles. These results clarified the regulatory role of GANP in targeting of cytidine
deaminase AID/APOBEC family proteins against the exogenous genetic invasion and alsoin protection of the host genome from DNA damages. Efficient targeting with APOBEC
cytidine deaminase would be essential for generation of non-infectious viruses in vivo, notonly for innate immunity but also for eliciting acquired immunological memory.

48

POSTER SESSION

TNF receptor-associated factor 5 inhibits Th17 differentiation
by antagonizing IL-6-receptor signaling
Hiroyuki Nagashima1, Yuko Okuyama1, Atsuko Asao1, Takeshi Kawabe1, Satoshi Yamaki1,
Hiroyasu Nakano2, Michael Croft3, Naoto Ishii1, Takanori So1
1

Department of Microbiology and Immunology, Tohoku University Graduate School of
Medicine, Japan; 2Department of Biochemistry, Toho University School of Medicine,Japan; 3Division of Immune Regulation, La Jolla Institute for Allergy and Immunology,USA
TNF receptor-associated factors (TRAFs) were initially discovered as adaptor proteinsthat couple the TNF receptor superfamily to downstream signaling pathways, but TRAFs
can regulate other pathways, such as from the Toll-like receptor family, the interleukin-1
receptor family, and the RIG-I-like receptor family. This suggests that TRAFs have avariety of functions in various contexts. We found that in the presence of IL-6 Traf5-/- naïve
CD4+ T cells displayed an increased ability to differentiate into Th17 cells. Consistent with
this, Th17-associated experimental autoimmune encephalomyelitis (EAE) was greatly
exaggerated in Traf5-/- mice. TRAF5 constitutively associated with a cytoplasmic region in
gp130 that overlaps with the STAT3 binding site and contains SXXE motif and two
di-acidic amino acids, which are recognition elements for the TRAF-C domain. The binding
between TRAF5 and gp130 suppressed the recruitment and activation of STAT3 in response
to IL-6. Our results uncover an unexpected molecular function of TRAF5. We are currently
examining if other TRAF proteins have a similar function in CD4+ T cell development.

49

POSTER SESSION

Role of Sox5 in the development of Th17 cells
Akira Suto
Department of Allergy and Clinical Immunology, Graduate School of Medicine,
Chiba University, Japan
Stat3 signaling is essential for the induction of RORt and subsequent Th17 celldifferentiation. However, the downstream targets of Stat3 for RORt expression remain
largely unknown. We show here that Sox5, named Sox5t, is induced in Th17 cells in a
Stat3-dependent manner. In vivo, T cell-specific Sox5-deficient mice exhibit impaired Th17
cell differentiation and are resistant to experimental autoimmune encephalomyelitis.
Retrovirus-mediated induction of Sox5 together with c-Maf induces Th17 celldifferentiation even in Stat3-deficient CD4+ T cells but not in RORt-deficient CD4+ T
cells, suggesting that Sox5t functions in downstream of IL-6-Stat3 signaling and upstreamof RORt expression during Th17 cell differentiation. Sox5 physically associates withc-Maf via the HMG domain of Sox5 and DNA-binding domain of c-Maf, and Sox5
together with c-Maf directly activates the promoter of RORt in CD4+ T cells. Taken
together, our results suggest that Sox5 and c-Maf cooperatively induce Th17 celldifferentiation via the induction of RORt as downstream targets of Stat3.

50

POSTER SESSION

C-terminal fragment of Clostridium perfringens enterotoxin is an efficientvaccine antigen delivery system for nasal pneumococcal vaccine.
Hidehiko Suzuki1, Jun Kunisawa1, 2
1

Laboratory of Vaccine Materials, National Institute of Biomedical Innovation, Japan
Division of Mucosal Immunology and International Research and Development Center for
Mucosal Vaccine, Institute of Medical Science, The University of Tokyo, Japan2

Mucosal vaccine can induce both systemic and mucosal immune responses and thus isconsidered to be an ideal vaccine for infectious diseases. In general, the efficient antigen
delivery to mucosal tissues, especially mucosa-associated lymphoid tissues (MALTs) isessential for the development of mucosal vaccine. We previously found that claudin-4 washighly expressed in nasopharynx-associated lymphoid tissue (NALT) andclaudin-4-targeting using C-terminal fragment of Clostridium perfringens enterotoxin(C-CPE) was an efficient antigen delivery system to NALT. In this study, we applied
C-CPE to mucosal vaccine against pneumonoccal infection. Pneumococcal surface proteinof A (PspA) is commonly expressed in S. pneumoniae and considered to be a vaccine
candidate. We genetically fused PspA and C-CPE (PspA-C-CPE) and confirmed that
PspA-C-CPE bound to claudin-4. Nasal immunization with PspA-C-CPE can induce
PspA-specific systemic and mucosal immune responses. Additionally, PspA-C-CPE canelicit protective immunity against pneumococcal infection. These findings indicate that
C-CPE is an efficient antigen delivery system for pneumococcal infection.

51

POSTER SESSION

Secondary IgM Antibody Response is Elicited from Low-affinity IgM+
Memory B cells but not High-affinity Ones.
Yasuyuki Tashiro1,2, Yasushi Hara1, Ryo Goitsuka2 and Takachika Azuma1
1

Laboratory of Structural Immunology, 2Division of Development and Aging, ResearchInstitute for Biomedical Sciences, Tokyo University of Science, Japan

Germinal center (GC) is considered as the site for class switch recombination(CSR) andsomatic hypermutation(SHM) in T-dependent (TD) response. Since IgG+ memory B cells
and Antibody Secreting Cells (ASCs) possess heavily mutated Ig genes, IgG+ B cells
develop mainly through GC-dependent pathway.
Recently it was reported that IgM+ memory B cells were also generated in TD immune
response. IgM+ memory B cells were mainly composed of clones with few SHMs and,
therefore, their development was independent on GC. Here we report that IgM+ GC B cells
possessing numerous Ig mutations resided in GC without maintaining IgM isotype usage.
These IgM+ GC B cells underwent affinity maturation, followed by memory B-celldevelopment. On the other hand, low-affinity IgM+ memory B cells were also generated
abundantly as reported previously. Surprisingly, high-affinity IgM+ GC B cells had poor
potential to develop into ASCs although high-affinity memory B cells were normallygenerated. In addition to GC B cells, high-affinity IgM+ memory B cells showed nocontribution to secondary IgM antibody response in contrast to normal production of
low-affinity IgM antibodies.
Secondary IgM response is elicited from low-affinity memory B cells but not
high-affinity ones, suggesting that these two types of IgM+ memory B cells play distinct
roles in secondary response. It remains elusive how high-affinity IgM+ memory B cells
function during the secondary response.

Memory B cell Generation
Low-affinity IgM+
memory B cells

AgAg

SHM / Affinity
ffinitynity Maturation
M
IgM+ B cell

Ag

GC

High-affinity IgM+
memory B cells?

52

ASC Formation

POSTER SESSION

C-type lectin Dectin-2 is a direct receptor
lipoarabinomannan that mediates its adjuvanticity.

formycobacterial

Akiko Yonekawa1,2, Sho Yamasaki1
1

Division of Molecular Immunology, Medical Institute of Bioregulation, Kyushu University,Japan
2
Department of Medicine and Biosystemic Science, Graduate School of Medical Sciences,
Kyushu University, Japan
Mycobacteria possess various characteristic cell-wall components, which affect the hostimmune responses. Mannose-capped lipoarabinomannan (Man-LAM) is a lipoglycan
derived from pathogenic mycobacteira and has long been known to have both inhibitoryand stimulatory activities on host immunity. However, the direct Man-LAM receptor that
explains its bidirectional effects have not been clearly identified.
Here, we show that a C-type lectin receptor Dectin-2 is a direct receptor for Man-LAM.
Man-LAM activated bone marrow-derived dendritic cells (BMDCs) to produce TNF,
whereas it was completely abrogated in Dectin-2–/– BMDCs. In addition, the IL-10 and IL-2
production was uniquely induced by Man-LAM in a Dectin-2-dependent manner.
Furthermore, Man-LAM stimulation promoted antigen-presenting cell functions throughDectin-2 on BMDCs. In a murine model of autoimmune disease, Man-LAM actuallyinduced experimental autoimmune encephalomyelitis (EAE) as an adjuvant throughDectin-2-FcR signaling axis.
These results demonstrate that Dectin-2 recognizes Man-LAM and play crucial roles inmediating the production of multiple cytokines and in vivo adjuvant activity.

53

~Speakers & Poster Presenters~
BURTON, Dennis

Department of Immunology andMicrobial Science, The Scripps
Research Instituteburton@scripps.edu

CROTTY, Shane

Division of Vaccine Discovery, La Jolla
Institute for Allergy and Immunology

shane@liai.org

HABU, Sonoko

Graduate School of Medicine,
Juntendo University

sonoko-h@juntendo.ac.jp

HARADA, Yohsuke

Research Institute for Biomedical
Sciences, Tokyo University of Science

yohsuke@rs.noda.tus.ac.jp

HIRAHARA, Kiyoshi

Graduate School of Medicine, Chiba
University

hiraharak@chiba-u.jp

HUANG, Yujun

Division of Developmental
Immunology, La Jolla Institute forAllergy and Immunology

yujun@liai.org

IIJIMA, Norifumi

Yale University School of Medicine

norifumi.iijima@yale.edu

ISE, Wataru

WPI Immunology Frontier ResearchCenter, Osaka University

wise@ifrec.osaka-u.ac.jp

ISHII, Ken J

National Institute of Biomedical
Innovation (NIBIO)/WPI Immunology Frontier ResearchCenter, Osaka University

kenishii@biken.osaka-u.ac.jp

KITAMURA, Daisuke

Research Institute for Biomedical
Sciences, Tokyo University of Sciencekitamura@rs.noda.tus.ac.jp

KIYONO, Hiroshi

The Institute of Medical Science, The
University of Tokyokiyono@ims.u-tokyo.ac.jp

KRONENBERG, Mitchell

Division of Developmental
Immunology, La Jolla Institute forAllergy & Immunology

mitch@liai.org

KUBO, Masato

Research Institute for Biomedical
Science, Tokyo University of Science/
RIKEN Center for Integrative Medical
Sciences (IMS)

raysolfc@rcai.riken.jp

KURACHI, Makoto

School of Medicine, University ofPennsylvania

kurachi@mail.med.upenn.edu

KUROSAKI, Tomohiro

WPI Immunology Frontier ResearchCenter, Osaka University/
RIKEN Center for Integrative Medical
Sciences (IMS)

kurosaki@ifrec.osaka-u.ac.jp

LEY, Klaus

Division of Inflammation Biology, La
Jolla Institute for Allergy and
Immunology

klaus@liai.org

54

MAEDA, KazuhikoDepartment of Immunology, Kumamoto kazmaeda@kumamoto-u.ac.jp
University

METZ, Patrick

Department of Medicine, University ofCalifornia, San Diegopmetz@ucsd.edu

MIYAZAKI, Masaki

Department of Biological Sciences,
University of California, San Diego

mmiyakai@ucsd.edu

NAGASHIMA, Hiroyuki

Tohoku University Graduate School of
Medicinenagashima.h@med.tohoku.ac.jp

NAKAYAMA, Toshinori

Graduate School of Medicine, Chiba
University

tnakayama@faculty.chiba-u.jp

PEARCE, Erika

Division of Immunobiology, Washington erikapearce@path.wustl.edu
University School of Medicine

PICKER, Louis

Vaccine and Gene Therapy Institute,Oregon Health and Science University

pickerl@ohsu.edu

PULENDRAN, Bali

Department of Pathology andLaboratory Medicine, Emory University
School of Medicine

bpulend@emory.edu

SAKAGUCHI, Nobuo

Graduate School of Medical Sciences,
School of Medicine, Kumamoto
University

nobusaka@kumamoto-u.ac.jp

SETTE, Alessandro

Division of Vaccine Discovery, La Jolla
Institute for Allergy and Immunology

alex@liai.org

SO, Takanori

Tohoku University Graduate School of
Medicine

tso@med.tohoku.ac.jp

SUTO, Akira

Graduate School of Medicine, Chiba
University

suaki@faculty.chiba-u.jp

SUZUKI, Hidehiko

National Institute of Biomedical
Innovation (NIBIO)

hide-suzuki@nibio.go.jp

TAKAMURA, Shiki

Kindai University Faculty of Medicine

takamura@med.kindai.ac.jp

TAKEDA, Kiyoshi

Graduate School of Medicine, Osaka
University

ktakeda@ongene.med.osaka-u.ac.jp

TASHIRO, Yasuyuki

RIBS, Tokyo University of Scienceta.yasuyuki@gmail.com

TOKOYODA, Koji

Deutsches
Rheuma-Forschungszentrum Berlin(DRFZ)

tokoyoda@drfz.de

UEMATSU, Satoshi

School of Medicine, Chiba University/
The Institute of Medical Science, The
University of Tokyo

suematsu@ims.u-tokyo.ac.jp55

VON ANDRIAN, Ulrich H.

Division of Immunology, Department ofMicrobiology and Immunobiology,
Harvard Medical School

uva@hms.harvard.edu

YOH, Sunnie

Immunity and Pathogenesis Program,
Sanford-Burnham Medical ResearchInstitute

yoh@sanfordburnham.org

YONEKAWA, Akiko

Medical Institute of Bioregulation,
Kyushu University

auehara@bioreg.kyushu-u.ac.jp

ZELLWEGER, Raphael

Division of Vaccine Discovery, La Jolla
Institute for Allergy and Immunologyraphael@liai.org

56

~IIMVF Members and Advisory Board~Core Members (Chairs)
KIYONO, Hiroshi

The Institute of Medical Science, The
University of Tokyokiyono@ims.u-tokyo.ac.jp

Graduate School of Medicine, Chiba
University

tnakayama@faculty.chiba-u.jp

Emory University School of Medicine

karaki@emory.edu

ISHII, Ken

National Institute of Biomedical
Innovation (NIBIO)IFREC, Osaka University

kenishii@biken.osaka-u.ac.jp

ISHII, Naoto

Tohoku University Graduate School of
Medicine

ishiin@med.tohoku.ac.jp

ISHIKAWA, Fumihiko

RIKEN Research Center for Allergy &Immunology

f_ishika@rcai.riken.jp

KAWAGUCHI, Yasushi

The Institute of Medical Science, The
University of Tokyoykawagu@ims.u-tokyo.ac.jp

KISHIMOTO, Hidehiro

Graduate School of Medicine,
University of the Ryukyus

hidek@med.u-ryukyu.ac.jp

KITAMURA, Daisuke

Research Institute for Biomedical
Sciences, Tokyo University of Sciencekitamura@rs.noda.tus.ac.jp

KUBO, Masato

Research Institute for Biomedical
Science, Tokyo University of Science/
RIKEN Center for Integrative Medical
Sciences (IMS)

raysolfc@rcai.riken.jp

KUNISAWA, Jun

National Institute of Biomedical
Innovation

kunisawa@nibio.go.jp

KURACHI, Makoto

University of Pennsylvania,
Microbiology

kurachi@mail.med.upenn.edu

KUROSAKI, Tomohiro

WPI Immunology Frontier ResearchCenter, Osaka University/
RIKEN Center for Integrative Medical
Sciences (IMS)

kurosaki@ifrec.osaka-u.ac.jp

MATSUSHIMA, Kouji

Graduate School of Medicine, The
University of Tokyokoujim@m.u-tokyo.ac.jp

MOTOHASHI, Shinichiro

Graduate School of Medicine, Chiba
University

motohashi@faculty.chiba-u.jp

NAKAJIMA, Hiroshi

Graduate School of Medicine, Chiba
University

nakajimh@faculty.chiba-u.jp

SAKAMOTO, Akemi

Graduate School of Medicine, Chiba
University

sakamoto@faculty.chiba-u.jp

NAKAYAMA, Toshinori
Core Members
ARAKI, Koichi

57

TAKAMURA, Shiki

Kindai University Faculty of Medicine

takamura@med.kindai.ac.jp

TAKEDA, Kiyoshi

Graduate School of Medicine, Osaka
University

ktakeda@ongene.med.osaka-u.ac.jp

TOKOYODA, Koji

Deutsches
Rheuma-Forschungszentrum Berlin(DRFZ)

tokoyoda@drfz.de

TOKUHISA, Takeshi

Chiba University

tokuhisa@faculty.chiba-u.jp

YAMAMOTO, Kazuhiko

Graduate School of Medicine, The
University of Tokyo

yamamoto-tky@umin.ac.jp

YAMASHITA, Masakatsu

Graduate School of Medicine, Ehime
University

yamamasa@m.ehime-u.ac.jp

YASUTOMO, Koji

Institute of Health Bioscience, The
University of Tokushima

yasutomo@tokushima-u.ac.jp

WPI Immunology Frontier ResearchCenter, Osaka University

sakira@biken.osaka-u.ac.jp

HABU, Sonoko

Graduate School of Medicine,
Juntendo University

sonoko-h@juntendo.ac.jp

INABA, Kayo

Graduate School of Biostudies, Kyoto
University

kayo@lif.kyoto-u.ac.jp

KARASUYAMA, Hajime

Tokyo Medical and Dental University
Graduate School

karasuyama.mbch@tmd.ac.jp

KAWAOKA, Yoshihiro

The Institute of Medical Science, The
University of Tokyo

kawaokay@svm.vetmed.wisc.edu

KOYASU, Shigeo

RIKEN Center for Integrative
Medical Sciences (IMS)

koyasu@z3.keio.jp

MINATO, Nagahiro

Graduate School of Medicine, Kyoto
University

minato@imm.med.kyoto-u.ac.jp

MIYASAKA, Masayuki

Institute for Academic Initiatives,
Osaka University

mmiyasak@orgctl.med.osaka-u.ac.jp

SAITO, Takashi

RIKEN Center for Integrative
Medical Sciences (IMS)saito@rcai.riken.jp

SAKAGUCHI, Nobuo

Graduate School of Medical Sciences,
School of Medicine, Kumamoto
University

nobusaka@kumamoto-u.ac.jp

SAKAGUCHI, Shimon

WPI Immunology Frontier ResearchCenter, Osaka University

shimon@ifrec.osaka-u.ac.jp

Advisors
AKIRA, Shizuo

58

SASAKAWA, Chihiro

Nippon Institute for Biological Science/ sasakawa@ims.u-tokyo.ac.jp
Medical Mycology Research Center(MMRC), Chiba University

SUGAMURA, Kazuo

Miyagi Prefectural Hospital
Organization

sugamura@med.tohoku.ac.jp

TAKEMORI, Toshitada

RIKEN Center for Integrative Medical
Sciences (IMS)

mttoshi@rcai.riken.jp

YAMANISHI, Koichi

National Institute of Biomedical
Innovation

yamanishi@nibio.go.jp

Emory Vaccine Center, Emory
University

rahmed@emory.edu

KRONENBERG, Mitchell

La Jolla Institute for Allergy &Immunology, Division of
Developmental Immunology

mitch@liai.org

PAUL, William

National Institute of Allergy and
Infectious Diseases, National
Institutes of Healthwpaul@niaid.nih.gov

PULENDRAN, Bali

Department of Pathology andLaboratory Medicine, Emory
University School of Medicine

bpulend@emory.edu

RADBRUCH, Andreas

Deutsches
Rheuma-Forschungszentrum Berlin(DRFZ)

radbruch@drfz.de

RAPPOULI, Rino

Novartis Vaccines & Diagnostics Srlrino.rappuoli@novartis.com

SCHOENBERGER, Stephen

La Jolla Institute for Allergy &Immunology

sps@liai.org

SHER, Alan

National Institute of Allergy and
Infectious Diseases, National
Institutes of Healthasher@niaid.nih.gov

International Advisors
AHMED, Rafi

59

The 2nd Symposium of International Immunological Memory and Vaccine Forum
August 25-26, 2014

Organized byInternational Immunological Memory and Vaccine Forum
US-Japan Cooperative Medical Sciences Program on Immunology
La Jolla Institute for Allergy & Immunology
Leading Graduate School at Chiba University
Chiba Innovation Program for Therapeutics at Chiba University
Organizing Committee
Mitchell Kronenberg, La Jolla Institute for Allergy & Immunology
Stephen Schoenberger, La Jolla Institute for Allergy & Immunology
Hiroshi Kiyono, The University of Tokyo
Toshinori Nakayama, Chiba University
Inquiries
International Immunological Memory and Vaccine Forum
Administrative OfficeTel: +81 43-226-2185 Fax: +81 43-227-1498
E-mail: hseo@chiba-u.jp
60

~ Thanks to ~Kyowa Hakko Kirin California, Inc.
Bay bioscience, Co., Ltd.
Becton, Dickinson and Company
BioLegend Japan KK
KEYENCE CORPORATIONRIKAKEN CO., LTD.
TOMY DIGITAL BIOLOGY CO., LTD.
YAKUKENSHA CO., LTD.

61International Immunological Memory and Vaccine Forum

Inquiries

Administrative OfficeTel: +81 43-226-2185
E-mail: hseo@chiba-u.jp

Fax: +81 43-227-1498