bluuebunny/crossref_metadata_2025_split huggingface dataset:
Redirecting antigen specificity to nonspecific CD8+25+ regular T cells through antigen-specific peptide/MHC complex arming. (P1085)
Authors: Wang Lu , Zhang Xueshu , Mulligan Sean , Xiang Jim 
Published: January 2023

Abstract
Compared with CD4+25+ regulatory T (Tr) cells, the mechanisms for immune suppression of natural CD8+25+ Tr cells are less studied. In this study, we demonstrate that CD8+25+ Tr cells inhibit in vitro T cell proliferation via cell-contact fashion, but independent upon expression of suppressive IL-10, TGF-β and CTLA-4. CD8+25+ Tr-treated T cells express CD73 and FR-4 and become resistant to cell proliferation by dendritic cell (DC) stimulation, whereas CD8+25+ Tr-treated DCs down-regulate expression of DC-maturation markers and inflammatory cytokines, and lack stimulatory effect on T cell proliferation. CD8+25+ Tr cells suppress ovalbumin (OVA)-pulsed DC (DCOVA)-stimulated CD8+ cytotoxic T lymphocyte (CTL) responses and antitumor immunity as well as myelin oligodendrocyte glycoprotein (MOG) peptide-induced experimental autoimmune encephalomyelitis (EAE). Importantly, CD8+25+ Tr cells, when pulsed with OVA323-339 and MOG35-55 peptide, exert enhanced inhibition of antitumor immunity and EAE, respectively. Interestingly, OVA323-339-pulsed (armed) CD8+25+ Tr cells also reduce CD4+ T cell interactions with DCOVA via increasing CD4+ T-cell velocities assessed by two-photon microscopy. Therefore, redirecting antigen specificity to nonspecific CD8+25+ Tr cells for enhanced immune suppression can be achieved via antigen-specific peptide/MHC complex arming. This principle may have great impact in natural Tr cell-mediated immunotherapy for autoimmune diseases.
NK cell licensing modulates NK cell conjugation to target cells via altered activation receptor function (P1063)
Authors: Thomas Louis , Long Eric 
Published: January 2023

Abstract
MHC class I recognition by inhibitory receptors on natural killer (NK) cells promotes a state of increased NK cell responsiveness through a process known as licensing/education. In the absence of either MHC class I expression or inhibitory receptors, NK cells exhibit a decreased responsive state. Thus NK cell licensing is a critical aspect of NK cell biology. However, understanding how licensing modulates natural cytotoxicity is limited. Using pure populations of unlicensed human NK cells, we were able to evaluate the effect of licensing on several NK cell functions. Our findings reveal that NK cell licensing does not affect lytic granule polarization but significantly enhances NK cell conjugation to target cells. Furthermore, our data show that activation receptors in unlicensed NK cells fail to provide strong ‘inside-out’ signaling for the beta2 integrin LFA-1. NK cell adhesion to target cells is a crucial initial step in NK cell-mediated cytotoxicity. The reduced conjugation of unlicensed NK cells may contribute to their hyporesponsive state.
Exploration and blockade of the decoy strategy: crystal structure of the LIGHT:DcR3 complex and rational design of DcR3 antagonists (P1067)
Authors: Liu Weifeng , Zhan Chenyang , Nathenson Stanley , Almo Steven 
Published: January 2023

Abstract
LIGHT is a member of the tumor necrosis factor (TNF) family that initiates intracellular signaling via engagement of the two TNF receptors HVEM and Lymphotoxin beta Receptor (LTbetaR). In humans, LIGHT is neutralized by a soluble TNF receptor denoted as decoy receptor 3 (DcR3), which tightly binds LIGHT and inhibits its interactions with HVEM and LTbetaR, resulting in blockade of the corresponding signaling pathways. In addition to LIGHT, DcR3 also binds and neutralizes two other TNF ligands, FasL and TL1A, thus further modulating the immune response. Because of its remarkable ability to neutralize three different ligands, DcR3 is thought to play an important role in regulating the immune response, especially in cancer immunology as suggested by elevated expression levels and the associated poor prognosis in cancer patients. However, the mechanisms that support the broad specificity of DcR3 (i.e., recognition of three different TNF ligands) remain to be fully defined. We have determined the structure of the LIGHT:DcR3 complex, revealing the structural basis for the DcR3-mediated neutralization of LIGHT. Comparison with our previously reported structure of the TL1A:DcR3 complex affords new insights into DcR3 function and selectivity. Based on these structures, we designed a novel LIGHT mutant that specifically recognizes DcR3 and exhibits no interaction with HVEM; this reagent dissects the multiple biochemical functions of LIGHT and offers unique clinical opportunities.
CD11c+ dendritic cells are required for IL-33-mediated expansion of ST2+Foxp3+ regulatory T cells in vivo (P1075)
Authors: Matta Benjamin , Lott Jeremy , Mathews Lisa , Rosborough Brian , Turnquist Heth 
Published: January 2023

Abstract
IL-33 is an IL-1 cytokine that signals via ST2, which is expressed on T cells and myeloid cells. Although IL-33 promotes Th2 responses, its administration potently expands CD4+Foxp3+ regulatory T cells (Treg). We examined if IL-33 expands murine Treg directly or indirectly through its impact on CD11c+ DC. The ability of IL-33 to facilitate CD3/CD28-stimulated proliferation of wild-type (WT) or ST2-/- Treg was compared to IL-2. The impact of IL-33 on the capacity of DC to expand Treg was defined in vitro on bone marrow (BM)-generated DC from WT or ST2-/- mice and in vivo using CD11c-DTR BM chimeras administered diphtheria toxin (DT) to deplete CD11c+ cells during IL-33 treatment. The capacity of IL-33-expanded Treg from Foxp3-RFP reporter mice to suppress effector T cells was assessed. We found that IL-33 directly expands Treg in vitro, including an ST2+ subset absent from IL-2-treated cultures. IL-33-exposed DC generate ST2+ Treg from naïve T cells, and is dependent on ST2 expressed by DC. IL-33 failed to expand Treg in vivo, especially ST2+ Treg, in the absence of CD11c+ cells. In conclusion, IL-33 promotes the expansion of suppressive Foxp3+ Treg, including an ST2+ subset in vitro and in vivo. This results from IL-33 activity directly on Treg, but more significantly, indirectly through its impact on CD11c+ cells. These findings have important implications for further characterization of ST2+ Treg and the development of novel therapeutics aimed at promoting immune tolerance.
Local changes in lipid environment of T cell receptor microclusters regulate membrane binding by the CD3epsilon cytoplasmic domain (P1103)
Authors: Gagnon Etienne , Wucherpfennig Kai 
Published: January 2023

Abstract
The CD3epsilon and zeta cytoplasmic domains of the T cell receptor bind to the inner leaflet of the plasma membrane, and a previous NMR structure showed that both tyrosines of the CD3epsilon Immuno-tyrosine based activation motif partition into the bilayer. Electrostatic interactions between acidic phospholipids and clusters of basic CD3epsilon residues were previously shown to be essential for CD3epsilon and zeta membrane binding. Phosphatidylserine is the most abundant negatively charged lipid on the inner leaflet of the plasma membrane and makes a major contribution to membrane binding by the CD3epsilon cytoplasmic domain. Here we show that T cell receptor triggering by peptide-MHC complexes induces dissociation of the CD3epsilon cytoplasmic domain from the plasma membrane. Release of the CD3epsilon cytoplasmic domain from the membrane is accompanied by a substantial focal reduction in negative charge and phosphatidylserine density in T cell receptor microclusters. The localized reduction in phosphatidylserine density is explained by reduced diffusion of this lipid into synapses. These changes in the lipid composition of T cell receptor microclusters even occur when receptor signaling is blocked with a Src kinase inhibitor. Local changes in the lipid composition of the microclusters thus render the CD3epsilon cytoplasmic domain accessible during early stages of T cell activation.
An altered relationship of influenza vaccine-specific IgG responses with T cell immunity occurs with aging in humans (P4293)
Authors: Lee Naeun , Kang Ki Soo , Shin Min Sun , Mohanty Subhasis , Belshe Robert B. , Montgomery Ruth R. , Shaw Albert C. , Kang Insoo 
Published: January 2023

Abstract
Alterations in T cell immunity occur with aging. Influenza causes significant morbidity and mortality in the elderly. We investigated the relationship of serum IgG responses with hemagglutinin inhibition (HI) antibody titers and the frequency of distinct T cell subsets in young and elderly people who received the inactivated influenza vaccine. Influenza vaccine-specific IgG responses correlated with the increase of HI antibody titers and the frequency of CD4+ T cells producing IFN-γ and IL-17 in young, but not elderly, people. Also, only in young people, such IgG responses correlated with the frequency of memory T cells, especially central memory cells, CD45RA- effector memory CD8+ T cells and IL-7 receptor alpha high effector memory CD8+ T cells with potent survival and proliferative capacity. These findings suggest that aging alters the association of influenza-vaccine specific IgG responses with HI antibody titers, cytokine-producing capacity and proportions of memory T cells in humans.
Influenza antigen microarrays reveal reactivity signatures associated with effective response to seasonal trivalent influenza vaccination (P4295)
Authors: Price Jordan , Jarrell Justin , Furman David , Kattah Nicole , Newell Evan , Dekker Cornelia , Davis Mark , Utz Paul 
Published: January 2023

Abstract
Existing methods to measure influenza vaccine immunogenicity prohibit detailed analysis of epitope determinants recognized by immunoglobulins. We developed influenza hemagglutinin (HA) whole-protein and peptide microarrays and validated that the arrays allow detection of specific antibody reactivity across a broad dynamic range using commercially available antibodies targeted to linear and conformational HA epitopes. In a cohort of 76 young and elderly subjects administered with the 2007/2008 trivalent influenza vaccine, we observed reactivity to influenza whole-protein and peptide array features that correlated significantly with age and post-vaccine titer as assessed through a standard microneutralization assay. One reactive peptide correlated positively with age and negatively with seasonal H1N1 neutralization titer, implicating reactivity to this epitope in age-related defects in response to H1N1 influenza. We also generated models based on age and pre-vaccine peptide reactivity that predicted vaccine-induced neutralization of seasonal H1N1 and H3N2 influenza strains with a high level of accuracy. Our methods provide powerful tools for rapid and accurate measurement of broad antibody-based immune responses to influenza, and may be useful in measuring response to other vaccines and infectious agents.
Cross-reactive influenza H1N1 T cell epitopes identified by immunoinformatic methods stimulate CD4+ T cell responses (P4303)
Authors: De Groot Anne , Boyle Christine , Ardito Matthew , Terry Frances , Latimer Howard , Tassone Ryan , Cote Mindy , Moise Leonard , Martin William 
Published: January 2023

Abstract
Immune responses to cross-conserved T cell epitopes in novel H1N1 influenza might explain reports of diminished influenza-like illnesses and confirmed infection among older adults, in the absence of cross-reactive humoral immunity, during the 2009 pandemic. We set out to identify and characterize cross-conserved H1N1 T cell epitopes to develop a universal H1N1 influenza vaccine. An immunoinformatic analysis was conducted using all available pandemic and pre-pandemic HA-H1 and NA-N1 sequences dating back to 1980. From 5,738 HA-H1 and 5,396 NA-N1 sequences, 13 HA and 4 NA immunogenic consensus sequences (ICS) were selected that each cover &gt;84% of pre-pandemic and pandemic H1N1 influenza strains, bear EpiMatrix scores ≥95th percentile and cover ≥4 HLA Class II archetypal alleles. HLA binding assays for 6 Class II archetypal alleles showed that immunoinformatic predictions were 78% accurate. Individual ICS peptides were immunoreactive in cultured human IFNy ELISpot assays after antigen-specific in vitro expansion. Intracellular cytokine staining showed the magnitude of IL-2, IFNy and/or TNFa expressing CD4+ T cells was boosted by 2011 seasonal trivalent influenza immunization for vaccine-matched and ICS HA peptide pools. Immunoinformatic methods identify cross-reactive influenza H1N1-specific CD4+ T cell epitopes. This approach can be applied to other influenza subtypes to develop a universal influenza vaccine that will protect against antigenically novel influenza viruses.
A quantitative explanation of vaccination for disease (P4315)
Authors: McAfee Megan , Johnson Philip , Antia Rustom , Blattman Joseph 
Published: January 2023

Abstract
Vaccination remains one of the most effective means for preventing infectious diseases. Vaccines encoding T cell epitopes have been proposed as a strategy for improving the efficacy of vaccines for chronic viral infections such as HIV. However, previous studies in mouse models of chronic viral infection have shown that vaccines eliciting narrowly focused T cell responses can result in enhanced disease. We have developed a quantitative framework for understanding how varying the precursor frequency of memory virus-specific CD8 T cells in naïve mice affects the balance between protection and pathology during subsequent infection with Lymphocytic Choriomeningitis virus. We have found that an intermediate precursor frequency of memory CD8 T cells results in maximum disease during subsequent infection. The transfer of a high number of memory CD8 T cells results in protection while low numbers undergo T cell exhaustion resulting in chronic infection. Enhancement of disease is not dependent on the breadth of the T cell response and is partially due to T cell production of TNF and IFNγ. In addition, decreased virus inoculum resulted in a lower precursor frequency of T cells needed to enhance disease. This suggests that for any given T cell response to vaccination there exists a viral dose that may result in enhanced disease. These studies highlight the importance of engaging multiple arms of the immune system during vaccination to maximize protection while minimizing pathology.
Poly gamma glutamic acid-chitosan nanogel dramatically enhances the protective efficacy and heterosubtypic cross-reactivity of H1N1 pandemic influenza vaccine in mice and ferrets (P4281)
Authors: Poo Haryoung 
Published: January 2023

Abstract
The global outbreak of 2009 H1N1 influenza pandemic emphasized the need for an effective vaccine adjuvant. Here, we examined the adjuvant efficacy of γ-PGA/chitosan nanogel (PC nanogel) for the 2009 H1N1 pandemic influenza vaccine antigen in mice and ferrets. Compared with alum, PC nanogel dramatically enhanced the protective efficacy of this vaccine, with animals exhibiting increased pandemic HA-specific antibody production, higher neutralization activity (HI titer), and earlier virus clearance from lung tissues after homologous (pandemic H1N1) and heterosubtypic (H3N2) viral challenges. In particular, approximately 4-fold higher influenza-specific cell-medicated immunity was observed in mice vaccinated with PC nanogel compared to alum, perhaps due to the dramatic enhancement of antigen uptake by immature dendritic cells. The results from T cell-depletion experiments indicated that the heterosubtypic cross-reactivity of PC nanogel was mediated by CD8+ T cells. Additionally, the long-lasting protection (100% at 6 months) against virus challenge after immunization and a one-twelfth dose-sparing effect were observed following vaccination with PC nanogel-adjuvanted vaccine but not with alum-adjuvanted vaccine. Together, these results strongly suggest that PC nanogel may be a promising candidate adjuvant for the influenza vaccine.
Mechanism for exploiting the complement 5a anaphylatoxin receptor on M cells by mucosal pathogen is closely related with that of mucosal immune induction (P3212)
Authors: Jang Yong-Suk , Kim Sae-Hae , Kim Ju , Choe Chung-Hyeon , Park Jisang , Lee Jeong-Chae , Kim Ji-Hae , Lee Kyung-Yeol 
Published: January 2023

Abstract
The mucosal epithelium is exposed to enormous amount of microorganisms containing commensal and pathogenic bacteria. Although many pathogens initiate their infection in mucosal epithelium and/or M cells of Peyer’s patch, detailed mechanism for the infection is poorly understood. We explored the possible survival mechanism of Yersinia enterocolitica in M cells in relation to crosstalk between C5aR and TLRs based on the observation that outermembrane protein H (OmpH) of Y. enterocolitica is one of the ligands for C5aR. Localization of C5aR and TLRs in human M-like cells and mouse M cells was confirmed during Y. enterocolitica infection. Also, regulation of cAMP- and/or autophagy-associated gene expression by Y. enterocolitica infection was characterized. Moreover, C5aR antagonist treatment reduced the survival of Y. enterocolitica in human M-like cells and the bacteria showed low infection efficiency in C5aR knock-out mouse. It is suggested that the OmpH of Y. enterocolitica could be used as M cell-targeting ligand in oral mucosal vaccination model. Collectively, we assume that the inhibition of cAMP expression by interaction between Y. enterocolitica and both C5aR and TLRs is closely associated with the bacterial survival in M cells and this interaction could be used as targeting of oral mucosal vaccine.
Th2-independent development of vaccine-enhanced disease associated with formalin-inactivated respiratory syncytial virus immunization (P3182)
Authors: Knudson Cory , Hartwig Stacey , Meyerholz David , Varga Steven 
Published: January 2023

Abstract
Respiratory syncytial virus (RSV) is the leading cause of lower respiratory tract infections in infants and there is currently no licensed RSV vaccine. Children immunized with a formalin-inactivated (FI) RSV vaccine during the 1960's exhibited exacerbated disease and increased mortality following a natural RSV infection. It is widely believed that a Th2-biased response directly contributes to the lung injury associated with FI-RSV vaccine-enhanced disease. This is in part due to the emphasis placed on the development of pulmonary eosinophilia noted in the autopsy reports from the FI-RSV vaccine trials. Furthermore, RSV challenge of FI-RSV-immunized mice results in extensive pulmonary inflammation including increased numbers of eosinophils and Th2 cytokine producing CD4 T cells. Depletion of CD4 T cells significantly ameliorates both airway resistance and weight loss associated with FI-RSV vaccine-enhanced disease. However, FI-RSV-immunized BALB/c mice genetically deficient in eosinophils elicit similar airway resistance, weight loss, and histopathology as compared to wild-type controls following RSV challenge. Moreover, FI-RSV-immunized STAT6-deficient mice exhibit significantly reduced Th2-associated responses, but similar airway resistance and weight loss as compared to wild-type controls following RSV challenge. Our results indicate that Th2 responses do not significantly contribute to critical disease parameters associated with FI-RSV vaccine-enhanced disease.
The effects of oral administration of silica nanoparticles on immunologic response to the food antigen (P3220)
Authors: Misato Kazuki , Yoshioka Yasuo , Uji Miyuki , Udaka Asako , Mori Takahide , Yamaguchi Manami , Hirai Toshiro , Yoshida Tokuyuki , Nabeshi Hiromi , Yoshikawa Tomoaki , Tsunoda Shin-ichi , Higashisaka Kazuma , Tsutsumi Yasuo 
Published: January 2023

Abstract
With the recent development of nanotechnology,nanomaterial (NM) with particle size below 100 nm have been developed and applied in various kinds of fields. For example, amorphous silica nanoparticles (nSP) have been already used in various foods as anticaking agents. Under this circumstance, there is increasing the importance of ensuring the safety of NM in foods. We previously revealed that nSP can penetrate the intestinal barrier, however,did not induce significant general toxicity. On the other hand, when we are exposed nSP, many food antigens are also exposed simultaneously.Thus, to ensure the safety of nSP, it is important to evaluate the effects of the oral exposure to nSP on immune response to food antigen. Here, we evaluated the effects of oral administration of nSP with a diameter of 30 nm on immunologic response to the food antigen. C3H/HeJ mice were orally administrated OVA or OVA plus nSP on days 0, 7, 14 and 21. Seven days after last administration, we measured OVA-specific antibody levels. Significant induction of OVA-specific IgG levels wasnot observed in OVA group compared with control. On the other hand, the mice administrated OVA plus nSP had significantly increased OVA-specific IgG levels compared with control groups. These results suggested that oral administration of nSP induced the abrogation of immune tolerance to food antigen. Currently, we are trying to evaluate the relationship between nSP and induction of food allergy.
Immunopathology in response to Vibrio parahaemolyticus infection. (P3222)
Authors: Parent Michelle , Read Kaitlin , Waters Stephanie , Guhl Shelby 
Published: January 2023

Abstract
Vibrio parahaemolyticus, is the most common cause of bacterial seafood-related illness in the United States. Infection results in a self-limiting gastrointestinal illness, wound infection or for those chronically ill, may lead to systemic infection and death. The CDC reports a 115% increase in laboratory confirmed cases of Vibrio species in 2012 as compared to 1996-1998 surveillance data, with an increase of 47% alone since 2011. A dearth of literature exists regarding characterization of host immunity to infection. Furthermore, a murine model of orogastric infection has not been available, prohibiting studies characterizing the host response to infection. Toward that end, employing a newly developed streptomycin-pretreatment orogastric model of infection, we have begun investigating host immunity to infection. Utilizing streptomycin pretreatment, we have established infection as confirmed by organism recovery from exposed tissue and by an influx of inflammatory cells to the site of infection as compared to control groups; therefore documenting immunopathology. Additionally, changes in mucin production and lactorferrin were also confirmatory of immunopathology. Lastly, we are investigating the pro-inflammatory response to infection by assessing IL-1β, IL-6, MIP-1α, MIP-1β. This novel orogastric murine model of infection will remove barriers, allowing for the identification of essential immune parameters required for controlling infection.