bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Replication Competent Adenovirus 5 Host Range Mutant-Simian Immunodeficiency Virus (SIV) Recombinant Priming/Subunit Protein Boosting Vaccine Regimen Induces Broad, Persistent SIV-Specific Cellular Immunity to Dominant and Subdominant Epitopes in Mamu-A*01 Rhesus Macaques
Authors: Malkevitch Nina , Patterson L. Jean , Aldrich Kristine , Richardson Ersell , Alvord W. Gregory , Robert-Guroff Marjorie 
Published: April 2014

Abstract
CTL are important in controlling HIV and SIV infection. To quantify cellular immune responses induced by immunization, CD8+ T cells specific for the subdominant Env p15m and p54m epitopes and/or the dominant Gag p11C epitope were evaluated by tetramer staining in nine macaques immunized with an adenovirus (Ad) 5 host range mutant (Ad5hr)-SIVenv/rev recombinant and in four of nine which also received an Ad5hr-SIVgag recombinant. Two Ad5hr-SIV recombinant priming immunizations were followed by two boosts with gp120 protein or an envelope polypeptide representing the CD4 binding domain. Two mock-immunized macaques served as controls. IFN-γ-secreting cells were also assessed by ELISPOT assay using p11C, p15m, and p54m peptide stimuli and overlapping pooled Gag and Env peptides. As shown by tetramer staining, Ad-recombinant priming elicited a high frequency of persistent CD8+ T cells able to recognize p11C, p15m, and p54m epitopes. The presence of memory cells 38 wk postinitial immunization was confirmed by expansion of tetramer-positive CD8+ T cells following in vitro stimulation. The SIV-specific CD8+ T cells elicited were functional and secreted IFN-γ in response to SIV peptide stimuli. Although the level and frequency of response of peripheral blood CD8+ T cells to the subdominant Env epitopes were not as great as those to the dominant p11C epitope, elevated responses were observed when lymph node CD8+ T cells were evaluated. Our data confirm the potency and persistence of functional cellular immune responses elicited by replication competent Ad-recombinant priming. The cellular immunity elicited is broad and extends to subdominant epitopes.
Up-Regulation of Cysteinyl Leukotriene 1 Receptor by IL-13 Enables Human Lung Fibroblasts to Respond to Leukotriene C4 and Produce Eotaxin
Authors: Chibana Kazuyuki , Ishii Yoshiki , Asakura Takuma , Fukuda Takeshi 
Published: April 2014

AbstractCysteinyl leukotrienes (CysLTs) play an important role in eosinophilic airway inflammation. In addition to their direct chemotactic effects on eosinophils, indirect effects have been reported. Eotaxin is a potent eosinophil-specific chemotactic factor produced mainly by fibroblasts. We investigated whether CysLTs augment eosinophilic inflammation via eotaxin production by fibroblasts. Leukotriene (LT)C4 alone had no effect on eotaxin production by human fetal lung fibroblasts (HFL-1). However, LTC4 stimulated eotaxin production by IL-13-treated fibroblasts, thereby indirectly inducing eosinophil sequestration. Unstimulated fibroblasts did not respond to LTC4, but coincubation or preincubation of fibroblasts with IL-13 altered the response to LTC4. To examine the mechanism(s) involved, the expression of CysLT1R in HFL-1 was investigated by quantitative real-time PCR and flow cytometry. Only low levels of CysLT1R mRNA and no CysLT1R protein were expressed in unstimulated HFL-1. In contrast, stimulation with IL-13 at a concentration of 10 ng/ml for 24 h significantly up-regulated both CysLT1R mRNA and protein expression in HFL-1. The synergistic effect of LTC4 and IL-13 on eotaxin production was abolished by CysLT1R antagonists pranlukast and montelukast. These findings suggest that IL-13 up-regulates CysLT1R expression, which may contribute to the synergistic effect of LTC4 and IL-13 on eotaxin production by lung fibroblasts. In the Th2 cytokine-rich milieu, such as that in bronchial asthma, CysLT1R expression on fibroblasts might be up-regulated, thereby allowing CysLTs to act effectively and increase eosinophilic inflammation.
Frequencies of Circulating Cytolytic, CD45RA+CD27−, CD8+ T Lymphocytes Depend on Infection with CMV
Authors: Kuijpers Taco W. , Vossen Mireille T. , Gent Mi-Ran , Davin Jean-Claude , Roos Marijke T. , Wertheim-van Dillen Pauline M. , Weel Jan F. , Baars Paul A. , van Lier Rene A. 
Published: April 2014

Abstract
Viral infections may cause serious disease unless the adaptive immune system is able to clear the viral agents through its effector arms. Recent identification and functional characterization of subpopulations of human CD8+ T cells has set the stage to study the correlation between the appearance of particular subsets and common viral infections during childhood, i.e., EBV, CMV, varicella-zoster virus (VZV), and the attenuated measles-mumps-rubella (MMR) vaccine strains. In a cohort of 220 healthy children we analyzed lymphocytes and subpopulations of CD4+ and CD8+ T cells. The presence of the cytolytic CD45RA+CD27− subset of CD8+ T cells correlated with prior CMV infection as defined by seroconversion (p &lt; 0.0001). The number of this CD8+ T cell subset remained stable during follow-up over 3 years in 40 children. The CD45RA+CD27− subset of CD8+ T cells first appeared during acute CMV infection and subsequently stabilized at an individual set-point defined by age and immunocompetence. The functional importance of these cells in CMV surveillance was reflected by their increased numbers in immunosuppressed pediatric kidney transplant patients. Preferential expansion of CD8+CD45RA+CD27− cytolytic T cells seems unique for CMV.
Cutting Edge: Increased NK Cell Activity in HIV-1-Exposed but Uninfected Vietnamese Intravascular Drug Users
Authors: Scott-Algara Daniel , Truong Lien X. , Versmisse Pierre , David Annie , Luong Tram T. , Nguyen Ngai V. , Theodorou Ioannis , Barré-Sinoussi Françoise , Pancino Gianfranco 
Published: April 2014

Abstract
We addressed the role of innate immunity in the protection against HIV-1 infection by studying NK cell function in 37 Vietnamese intravascular drug users (IDUs), who appeared to remain HIV-1 uninfected despite many years of high-risk exposure (exposed uninfected, EU), 10 IDUs who underwent seroconversion and 28 unexposed blood donors. Main results were: NK cell lytic activities against both the NK-susceptible K562 cell line and the NK-resistant Daudi cell line were significantly augmented in EU IDUs compared with either controls or seroconverters before or after seroconversion; NK cells producing the cytokines IFN-γ and TNF-α and the β chemokines CCL3, CCL4, and CCL5 were also increased in the EU IDUs, either after in vitro activation or without stimulation. The finding of an enhanced NK cell function in EU IDUs, especially compared with IDUs who became HIV-1 infected, supports the hypothesis that NK cells contribute to the protection against HIV-1 infection.
Cutting Edge: TCR Contacts as Anchors: Effects on Affinity and HLA-DM Stability
Authors: Anderson Matthew W. , Gorski Jack 
Published: April 2014

AbstractPeptides presented via the class II MHC (MHCII) pathway are selected based on affinity for MHCII and stability in the presence of HLA-DM. Currently, epitope selection is thought to be controlled by the ability of peptide to sequester “anchor” residues into pockets in the MHCII. Residues exhibiting higher levels of solvent accessibility have been shown to contact TCR, but their roles in affinity and complex stability have not been directly studied. Using the HLA-DR1-binding influenza peptide, hemagglutinin (306–318), as a model, we show that side chain substitutions at these positions influence affinity and HLA-DM stability. Multiple substitutions reduce affinity to a greater extent than the loss of the major P1 anchor residue. We propose that these effects may be mediated through the H-bond network. These results demonstrate the importance of solvent-exposed residues in epitope selection and blur the distinctions between anchor and TCR contact residues.
Requirements for T Cell-Polarized Tubulation of Class II+ Compartments in Dendritic Cells
Authors: Bertho Nicolas , Cerny Jan , Kim You-Me , Fiebiger Edda , Ploegh Hidde , Boes Marianne 
Published: April 2014

Abstract
Activation of naive CD4 T cells by dendritic cells requires the sequential interaction of many TCR molecules with peptide-class II complexes of the appropriate specificity. Such interaction results in morphological transformation of class II MHC-containing endosomal compartments. In this study, we analyze the requirements for long tubular endosomal structures that polarize toward T cell contact sites using dendritic cells from I-Ab class II -enhanced green fluorescent protein knock-in mice and I-Ab-restricted CD4 T cells specific for OVA. Clustering of membrane proteins and ligation of T cell adhesion molecules LFA-1 and CD2 are involved in induction of endosomal tubulation. Activation of T cells increases their ability to induce class II-enhanced green fluorescent protein-positive tubules in dendritic cells, in part through up-regulation of CD40 ligand. Remarkably, and in stark contrast with the result obtained with dendritic cells loaded with intact OVA, OVA peptide added to dendritic cells failed to evoke T cell-polarized endosomal tubulation even though both conditions allowed T cell stimulation. These results suggest the existence of microdomains on the membrane of dendritic cells that allow Ag-specific T cells to evoke tubulation in the dendritic cell.
IL-2 Is Not Required for the Initiation of CD8 T Cell Cycling but Sustains Expansion
Authors: D’Souza Warren N. , Lefrançois Leo 
Published: April 2014

AbstractBased primarily on in vitro data, IL-2 is believed to be the key cytokine for initiation of the cell cycle of activated T cells. However, the role of IL-2 remains unresolved for T cell responses in vivo. We examined whether the absence of IL-2-mediated signaling in CD8 T cells affected initiation of proliferation. Our results conclusively demonstrated that initial division of Ag-specific CD8 T cells following priming was IL-2 independent, regardless of the context in which Ag was presented. In contrast, the latter stage of the proliferative phase was IL-2-dependent, particularly in nonlymphoid tissues. Thus, activated CD8 T cells initially undergo IL-2-independent proliferation, but reach a critical juncture where the requirement for IL-2 as a growth factor gains prominence.
Dendritic Cell-Induced Activation of Adaptive and Innate Antitumor Immunity
Authors: van den Broeke Leon T. , Daschbach Emily , Thomas Elaine K. , Andringa Gerda , Berzofsky Jay A. 
Published: April 2014

AbstractWhile studying Ag-pulsed syngeneic dendritic cell (DC) immunization, we discovered that surprisingly, unpulsed DCs induced protection against tumor lung metastases resulting from i.v. injection of a syngeneic BALB/c colon carcinoma CT26 or a syngeneic C57BL/6 lung carcinoma LL/2. Splenocytes or immature splenic DCs did not protect. The protection was mediated by NK cells, in that it was abrogated by treatment with anti-asialo-GM1 but not anti-CD8, and was induced by CD1−/− DCs unable to stimulate NKT cells, but did not occur in beige mice lacking NK cells. Protection correlated with increased NK activity, and increased infiltration of NK but not CD8+ cells in lungs of tumor-bearing mice. Protection depended on the presence of costimulatory molecules CD80, CD86, and CD40 on the DCs, but surprisingly did not require DCs that could make IL-12 or IL-15. Unexpectedly, protection sensitive to anti-asialo-GM1 and increased NK activity were still present 14 mo after DC injection. As NK cells lack memory, we found by depletion that CD4+ not CD8+ T cells were required for induction of the NK antitumor response. The role of DCs and CD4+ T cells provides a novel mechanism for NK cell induction and innate immunity against cancer that may have potential in preventing clinical metastases.
Ligation of CD27 on B Cells In Vivo during Primary Immunization Enhances Commitment to Memory B Cell Responses
Authors: Raman Vanitha S. , Akondy Rama S. , Rath Satyajit , Bal Vineeta , George Anna 
Published: April 2014

AbstractLigation of CD27 on B cells has been shown to inhibit terminal differentiation of activated murine B cells into plasma cells. We show in this study that this inhibition is accompanied by an enhanced movement of activated B cells toward differentiation into memory cells. Treatment of mice with anti-CD27 during immunization leads to the generation of greater numbers of Ag-binding B cells in draining lymph nodes that persist for longer periods of time, and they contain a greater proportion of cells of a postgerminal center phenotype. Limiting dilution analyses reveal that they contain a higher frequency of cells that can be stimulated to secrete specific IgG, and adoptive transfer experiments confirm that they can generate higher secondary responses in carrier-primed recipients. Remarkably, significant secondary responses are also seen following primary immunization with a T-independent Ag in the presence of anti-CD27, confirming that ligation of CD27 on B cells during priming induces differentiation into the memory lineage. Treatment with anti-CD27 during priming also increases the average affinity of the secondary response, suggesting that high affinity clones generated early in a primary response may normally differentiate preferentially into plasma cells and are rescued from this fate by CD27 ligation. Anti-CD40 treatment shows similar effects in vivo. However, unlike CD27, CD40 coligation also enhances proliferation, survival, and isotype switching of LPS-stimulated B cells, suggesting that the two receptors may enhance commitment to B cell memory by different mechanisms, or that a common mechanism is used through both receptors that does not involve cell cycle control or survival.
Tolerance through Indifference: Autoreactive B Cells to the Nuclear Antigen La Show No Evidence of Tolerance in a Transgenic Model
Authors: Aplin Brett D. , Keech Catherine L. , de Kauwe Andrea L. , Gordon Thomas P. , Cavill Dana , McCluskey James 
Published: April 2014

AbstractSystemic autoimmune diseases are characterized by the production of high titer autoantibodies specific for ubiquitous nuclear self-Ags such as DNA, Sm, and La (SS-B), so the normal mechanisms of B cell tolerance to disease-associated nuclear Ags have been of great interest. Mechanisms of B cell tolerance include deletion, anergy, developmental arrest, receptor editing, and B cell differentiation to the B-1 subtype. However, recent studies in our laboratory have suggested that B cell tolerance to the nuclear autoantigen La is limited in normal mice, and tolerance may reside primarily in the T cell compartment. To test this hypothesis, we created Ig transgenic mice expressing the IgM H chain from an mAb specific for a xenogeneic epitope within human La (hLa). These mice were bred with hLa-transgenic mice that constitutively express hLa in a manner comparable to endogenous mouse La. Between 5–15% of transgenic B cells developing in the absence of hLa were specific for hLa, and these cells were neither depleted nor developmentally arrested in the presence of endogenous hLa expression. Instead, these autoreactive B cells matured normally and differentiated into Ab-forming cells, capable of secreting high titer autoantibody. Additionally, the life span of autoreactive hLa-specific B cells was not reduced, and they were phenotypically and functionally indistinguishable from naive nonautoreactive hLa-specific B cells developing in the absence of hLa. Together these data suggest a lack of intrinsic B cell tolerance involving any known mechanisms indicating that these autoreactive B cells are indifferent to their autoantigen.
Vaccination with Plasmid DNA Activates Dendritic Cells via Toll-Like Receptor 9 (TLR9) but Functions in TLR9-Deficient Mice
Authors: Spies Barbara , Hochrein Hubertus , Vabulas Martin , Huster Katharina , Busch Dirk H. , Schmitz Frank , Heit Antje , Wagner Hermann 
Published: April 2014

AbstractWe analyzed whether the immunobiology of vaccinating plasmid DNA containing a transcription unit for OVA is influenced by immunostimulatory CpG motifs in the plasmid backbone. Indeed, plasmid DNA differentially activated in vitro myeloid and plasmacytoid dendritic cells (DCs) provided they expressed the CpG-DNA receptor, Toll-like receptor 9 (TLR9). Dependent on the DC subset, activation resulted in type 1 IFN production, while both DC subsets produced IL-6 and up-regulated expression of costimulatory molecules CD40 and CD86. In vivo, however, even upon repeated vaccination with plasmid DNA, priming of OVA-specific CTL and clonal expansion of SIINFEKL-specific CD8 T cells were equal in TLR9-positive and TLR9- or MyD88-negative mice. Overall, these results negate a dominant role of CpG-DNA/TLR9 interactions in long-term vaccination protocols.
CD19 Function in Early and Late B Cell Development. II. CD19 Facilitates the Pro-B/Pre-B Transition
Authors: Otero Dennis C. , Rickert Robert C. 
Published: April 2014

AbstractProliferative expansion of pro-B cells is an IL-7-dependent process that allows for the rearrangement of H chain genes and the expression of the pre-B cell receptor (pre-BCR). Further B cell differentiation is dependent upon signals elicited through the pre-BCR, which are thought to be responsible for allelic exclusion, induced L chain gene rearrangement, and continued proliferation. CD19 promotes the proliferation and survival of mature B cells, but its role in early B cell development is less well understood. Here we identify and characterize impairments in early B cell development in CD19−/− mice. Following sublethal irradiation, we found decreased numbers of autoreconstituted early B cells, which was first evident in the large cycling pre-B cell fraction. Reduced cell progression due to a defect in proliferation was made evident from cell cycle analysis and bromodeoxyuridine labeling of bone marrow cells from CD19−/− and wild-type mice. Studies of IL-7-dependent pre-B cell cultures derived from wild-type and CD19−/− mouse bone marrow suggested that CD19 has little affect on IL-7 signaling. By contrast, signaling through the pre-BCR was impaired in the absence of CD19, as demonstrated by reduced activation of Bruton’s tyrosine kinase and extracellular signal-regulated kinase/mitogen-activated protein kinase. Thus, in addition to promoting mature B cell homeostasis and Ag-induced responses, the early onset of CD19 expression acts to enhance B cell generation.
Dendritic Cells Charged with Apoptotic Tumor Cells Induce Long-Lived Protective CD4+ and CD8+ T Cell Immunity against B16 Melanoma
Authors: Goldszmid Romina S. , Idoyaga Juliana , Bravo Alicia I. , Steinman Ralph , Mordoh José , Wainstok Rosa 
Published: April 2014

AbstractDendritic cells (DCs) are potent APCs and attractive vectors for cancer immunotherapy. Using the B16 melanoma, a poorly immunogenic experimental tumor that expresses low levels of MHC class I products, we investigated whether DCs loaded ex vivo with apoptotic tumor cells could elicit combined CD4+ and CD8+ T cell dependent, long term immunity following injection into mice. The bone marrow-derived DCs underwent maturation during overnight coculture with apoptotic melanoma cells. Following injection, DCs migrated to the draining lymph nodes comparably to control DCs at a level corresponding to ∼0.5% of the injected inoculum. Mice vaccinated with tumor-loaded DCs were protected against an intracutaneous challenge with B16, with 80% of the mice remaining tumor-free 12 wk after challenge. CD4+ and CD8+ T cells were efficiently primed in vaccinated animals, as evidenced by IFN-γ secretion after in vitro stimulation with DCs loaded with apoptotic B16 or DCs pulsed with the naturally expressed melanoma Ag, tyrosinase-related protein 2. In addition, B16 melanoma cells were recognized by immune CD8+ T cells in vitro, and cytolytic activity against tyrosinase-related protein 2180–188-pulsed target cells was observed in vivo. When either CD4+ or CD8+ T cells were depleted at the time of challenge, the protection was completely abrogated. Mice receiving a tumor challenge 10 wk after vaccination were also protected, consistent with the induction of tumor-specific memory. Therefore, DCs loaded with cells undergoing apoptotic death can prime melanoma-specific helper and CTLs and provide long term protection against a poorly immunogenic tumor in mice.
Altered Regulation of FcγRII on Aged Follicular Dendritic Cells Correlates with Immunoreceptor Tyrosine-Based Inhibition Motif Signaling in B Cells and Reduced Germinal Center Formation
Authors: Aydar Yüksel , Balogh Péter , Tew John G. , Szakal Andras K. 
Published: April 2014

AbstractAging is associated with reduced trapping of Ag in the form of in immune complexes (ICs) by follicular dendritic cells (FDCs). We postulated that this defect was due to altered regulation of IC trapping receptors. The level of FDC-M1, complement receptors 1 and 2, FcγRII, and FDC-M2 on FDCs was immunohistochemically quantitated in draining lymph nodes of actively immunized mice for 10 days after Ag challenge. Initially, FDC FcγRII levels were similar but by day 3 a drastic reduction in FDC-FcγRII expression was apparent in old mice. FDC-M2 labeling, reflecting IC trapping, was also reduced and correlated with a dramatic reduction in germinal center (GC) B cells as indicated by reduced GC size and number. Nevertheless, labeling of FDC reticula with FDC-M1 and anti-complement receptors 1 and 2 was preserved, indicating that FDCs were present. FDCs in active GCs normally express high levels of FcRs that are thought to bind Fc portions of Abs in ICs and minimize their binding to FcRs on B cells. Thus, cross-linking of B cell receptor and FcR via IC is minimized, thereby reducing signaling via the immunoreceptor tyrosine-based inhibition motif. Old FDCs taken at day 3, when they lack FcγRII, were incapable of preventing immunoreceptor tyrosine-based inhibition motif signaling in wild-type B cells but old FDCs stimulated B cells from FcγRIIB−/− mice to produce near normal levels of specific Ab. The present data support the concept that FcR are regulated abnormally on old FDCs. This abnormality correlates with a reduced IC retention and with a reduced capacity of FDCs to present ICs in a way that will activate GC B cells.
Ikaros Family Members from the Agnathan Myxine glutinosa and the Urochordate Oikopleura dioica: Emergence of an Essential Transcription Factor for Adaptive Immunity
Authors: Cupit Pauline M. , Hansen John D. , McCarty Aaron S. , White Greg , Chioda Mariacristina , Spada Fabio , Smale Stephen T. , Cunningham Charles 
Published: April 2014

Abstract
The Ikaros multigene family encodes a number of zinc finger transcription factors that play key roles in vertebrate hemopoietic stem cell differentiation and the generation of B, T, and NK cell lineages. In this study, we describe the identification and characterization of an Ikaros family-like (IFL) protein from the agnathan hagfish Myxine glutinosa and the marine urochordate Oikopleura dioica, both of which lie on the evolutionary boundary between the vertebrates and invertebrates. The IFL molecules identified in these animals displayed high conservation in the zinc finger motifs critical for DNA binding and dimerization in comparison with those of jawed vertebrates. Expression of the IFL gene in hagfish was strongest in blood, intestine, and gills. In O. dioica, transcription from the IFL gene was initiated at or around the time of hatching and maintained throughout the life span of the animal. In situ hybridization localized O. dioica IFL expression to the Fol cells, which are responsible for generating the food filter of the house. Biochemical analysis of the DNA binding and dimerization domains from M. glutinosa and O. dioici IFLs showed that M. glutinosa behaves as a true Ikaros family member. Taken together, these results indicate that the properties associated with the Ikaros family preceded the emergence of the jawed vertebrates and thus adaptive immunity.