bluuebunny/crossref_metadata_2025_split huggingface dataset:
Molecular Mechanisms for Gender Differences in Susceptibility to T Cell-Mediated Autoimmune Diabetes in Nonobese Diabetic Mice
Authors: Bao Min , Yang Yang , Jun Hee-Sook , Yoon Ji-Won 
Published: April 2014

Abstract
Nonobese diabetic (NOD) mice spontaneously develop diabetes with a strong female prevalence; however, the mechanisms for this gender difference in susceptibility to T cell-mediated autoimmune diabetes are poorly understood. This investigation was initiated to find mechanisms by which sex hormones might affect the development of autoimmune diabetes in NOD mice. We examined the expression of IFN-γ, a characteristic Th1 cytokine, and IL-4, a characteristic Th2 cytokine, in islet infiltrates of female and male NOD mice at various ages. We found that the most significant difference in cytokine production between sexes was during the early stages of insulitis at 4 wk of age. IFN-γ was significantly higher in young females, whereas IL-4 was higher in young males. CD4+ T cells isolated from lymph nodes of female mice and activated with anti-CD3 and anti-CD28 Abs produced more IFN-γ, but less IL-4, as compared with males. Treatment of CD4+ T cells with estrogen significantly increased, whereas testosterone treatment decreased the IL-12-induced production of IFN-γ. We then examined whether the change in IL-12-induced IFN-γ production by treatment with sex hormones was due to the regulation of STAT4 activation. We found that estrogen treatment increased the phosphorylation of STAT4 in IL-12-stimulated T cells. We conclude that the increased susceptibility of female NOD mice to the development of autoimmune diabetes could be due to the enhancement of the Th1 immune response through the increase of IL-12-induced STAT4 activation by estrogen.
Cutting Edge: A-Kinase Anchor Proteins Are Involved in Maintaining Resting T Cells in an Inactive State
Authors: Williams Richard O. 
Published: April 2014

Abstract
A-kinase anchor proteins (AKAPs) target protein kinase A (PKA) to different subcellular locations and are thought to play important roles in the cAMP signaling pathway. The aims of this study were to determine whether T cells express AKAPs and, if so, to establish their physiological significance. CD4+ T cells were found to express eight AKAPs. Disruption of the AKAP-PKA interaction caused high levels of IL-2, IL-4, IL-5, and IFN-γ production in the absence of stimulation via CD3ε and CD28 molecules. Disruption of the AKAP-PKA interaction acted synergistically with suboptimal doses of Ag in boosting proliferative responses of T cells. Finally, disruption of the AKAP-PKA interaction rendered T cells insensitive to cAMP-elevating agents. It was concluded that AKAPs, through their association with PKA, are involved in maintaining T cell homeostasis and in regulating the sensitivity of T cells to incoming cAMP signals.
Ligation of HLA Class I Molecules on Endothelial Cells Induces Phosphorylation of Src, Paxillin, and Focal Adhesion Kinase in an Actin-Dependent Manner
Authors: Jin Yi-Ping , Singh Ram Pyare , Du Ze-Ying , Rajasekaran Ayyappan K. , Rozengurt Enrique , Reed Elaine F. 
Published: April 2014

AbstractThe development of chronic rejection is the major limitation to long-term allograft survival. HLA class I Ags have been implicated to play a role in this process because ligation of class I molecules by anti-HLA Abs stimulates smooth muscle cell and endothelial cell proliferation. In this study, we show that ligation of HLA class I molecules on the surface of human aortic endothelial cells stimulates phosphorylation of Src, focal adhesion kinase, and paxillin. Signaling through class I stimulated Src phosphorylation and mediated fibroblast growth factor receptor (FGFR) translocation to the nucleus. In contrast, Src kinase activity was not involved in class I-mediated transfer of FGFR from cytoplasmic stores to the cell surface. Inhibition of Src protein kinase activity blocked HLA class I-stimulated tyrosine phosphorylation of paxillin and focal adhesion kinase. Furthermore, HLA class I-mediated phosphorylation of the focal adhesion proteins and FGFR expression was inhibited by cytochalasin D and latrunculin A, suggesting a role for the actin cytoskeleton in the signaling process. These findings indicate that anti-HLA Abs have the capacity to transduce activation signals in endothelial cells that may promote the development of chronic rejection.
IL-23 and IL-12 Have Overlapping, but Distinct, Effects on Murine Dendritic Cells
Authors: Belladonna Maria Laura , Renauld Jean-Christophe , Bianchi Roberta , Vacca Carmine , Fallarino Francesca , Orabona Ciriana , Fioretti Maria Cristina , Grohmann Ursula , Puccetti Paolo 
Published: April 2014

AbstractIL-23 is a recently discovered heterodimeric cytokine that shares biological properties with proinflammatory cytokines. The biologically active heterodimer consists of p19 and the p40 subunit of IL-12. IL-23 has been shown to possess biological activities on T cells that are similar as well distinct from those of IL-12. We have constructed single-chain IL-23 and IL-12 fusion proteins (IL-23-Ig and IL-12-Ig) and have compared the two recombinant proteins for effects on murine dendritic cells (DC). Here we show that the IL-23-Ig can bind a significant proportion of splenic DC of both the CD8α− and CD8α+ subtypes. Furthermore, IL-23and IL-12-Ig exert biological activities on DC that are only in part overlapping. While both proteins induce IL-12 production from DC, only IL-23-Ig can act directly on CD8α+ DC to promote immunogenic presentation of an otherwise tolerogenic tumor peptide. In addition, the in vitro effects of IL-23-Ig did not appear to require IL-12Rβ2 or to be mediated by the production of IL-12. These data may establish IL-23 as a novel cytokine with major effects on APC.
Complementary Roles for CD19 and Bruton’s Tyrosine Kinase in B Lymphocyte Signal Transduction
Authors: Fujimoto Manabu , Poe Jonathan C. , Satterthwaite Anne B. , Wahl Matthew I. , Witte Owen N. , Tedder Thomas F. 
Published: April 2014

AbstractCD19 and Bruton’s tyrosine kinase (Btk) may function along common signaling pathways in regulating intrinsic and B cell Ag receptor (BCR)-induced signals. To identify physical and functional interactions between CD19 and Btk, a CD19-negative variant of the A20 B cell line was isolated, and CD19-deficient (CD19−/−) and CD19-overexpressing mice with the X-linked immunodeficient (Xid; Btk) mutation were generated. In A20 cells, Btk physically associated with CD19 following BCR engagement. CD19 and Btk interactions were not required for initial Btk phosphorylation, but CD19 expression maintained Btk in an activated state following BCR engagement. In primary B cells, CD19 signaling also required downstream Btk function since CD19-induced intracellular Ca2+ ([Ca2+]i) responses were modest in Xid B cells. In addition, CD19 overexpression did not normalize the Xid phenotype and most phenotypic and functional hallmarks of CD19 overexpression were not evident in these mice. However, CD19 and Btk also regulate independent signaling pathways since their combined loss had additive inhibitory effects on BCR-induced [Ca2+]i responses and CD19 deficiency induced a severe immunodeficiency in Xid mice. Thus, CD19 expression amplifies or prolongs Btk-mediated signaling, rather than serving as a required agent for Btk activation. Consistent with this, phosphatidylinositol 3-monophosphate kinase and Akt activation were normal in CD19−/− B cells following IgM engagement, although their kinetics of activation was altered. Thus, these biochemical and compound gene dosage studies indicate that Btk activation and [Ca2+]i responses following BCR engagement are regulated through multiple pathways, including a CD19/Src family kinase-dependent pathway that promotes the longevity of Btk signaling.
Stimulation Through Intercellular Adhesion Molecule-1 Provides a Second Signal for T Cell Activation
Authors: Chirathaworn Chintana , Kohlmeier Jacob E. , Tibbetts Scott A. , Rumsey Lisa M. , Chan Marcia A. , Benedict Stephen H. 
Published: April 2014

AbstractRegulation of T cell activation requires two signals. First, appropriately presented Ag in the context of MHC interacts with the T cell Ag receptor-CD3 complex. The best-studied second signal is CD28, which resides on the T cell and responds to its counter receptor, B7. A second signal also can be delivered through LFA-1 residing on the T cell, responding to its counter receptor ICAM-1 residing on a different cell. Characterization of a second signal is tied to its ability to costimulate (along with stimulation through the TCR) proliferation, IL-2 secretion, and coactivation of phosphatidylinositol 3-kinase. We examined whether ICAM-1, residing on the T cell surface, could deliver a second signal into that T cell. Costimulation through CD3 plus ICAM-1 caused increased T cell proliferation, increased expression of the activation marker CD69, increased transcription through the IL-2 regulatory region, and increased secretion of selected Th1 but not Th2 cytokines. Costimulation through CD3 plus ICAM-1 caused synergistic activation of phosphatidylinositol 3-kinase. Finally, the combination of anti-CD3 plus anti-ICAM-1 (but not anti-CD3 alone) caused prolonged proliferation of naive T cells in a manner similar to costimulation through LFA-1 or CD28. Thus, we demonstrate for the first time that ICAM-1 resident on a T cell can deliver a costimulatory signal into that T cell.
Essential Role for IL-2 in the Regulation of Antiviral Extralymphoid CD8 T Cell Responses
Authors: D’Souza Warren N. , Schluns Kimberly S. , Masopust David , Lefrançois Leo 
Published: April 2014

AbstractIL-2 is a cytokine produced primarily by activated T cells and is thought to be the quintessential T cell growth factor. The precise role of IL-2 in the regulation of CD8 T cell responses to foreign Ag in vivo however remains enigmatic. Using an adoptive transfer system with IL-2- or IL-2R-deficient TCR transgenic CD8 T cells and MHC class I tetramers, we demonstrated that the expansion of antiviral CD8 T cells in secondary lymphoid tissues was IL-2 independent, whereas IL-2 played a more significant role in supporting the continued expansion of these cells within nonlymphoid tissues. Paradoxically, autocrine IL-2 negatively regulated the overall magnitude of the CD8 T cell response in nonlymphoid tissues via a Fas-independent mechanism. Furthermore, autocrine IL-2 did not regulate the contraction or memory phase of the response. These experiments identified a novel role for IL-2 in regulation of antiviral CD8 T cell responses and homeostasis in nonlymphoid tissues.
Induction of Macrophage-Inflammatory Protein-3α Gene Expression by TNF-Dependent NF-κB Activation
Authors: Sugita Shinichi , Kohno Tomoko , Yamamoto Kazuo , Imaizumi Yoshitaka , Nakajima Hisayoshi , Ishimaru Tadayuki , Matsuyama Toshifumi 
Published: April 2014

AbstractMacrophage-inflammatory protein-3α (MIP-3α), also designated as liver and activation-regulated chemokine (LARC), Exodus, or CCL20, is a recently identified CC chemokine that is expected to play a crucial role in the initiation of immune responses. In this study, we describe that MIP-3α expression is under the direct control of NF-κB, a key transcription factor of immune and inflammatory responses. Overexpression of the p65/RelA subunit of NF-κB significantly increased the MIP-3α mRNA level. MIP-3α transcription was stimulated by TNF, and this stimulation was inhibited by an NF-κB inhibitor, I-κBα superrepressor. Analysis of the human MIP-3α promoter demonstrated a functional NF-κB site responsible for its expression. We also show that MIP-3α expression is induced in LPS-treated mouse livers that were primed with Propionibacterium acnes, which developed massive liver injury with infiltration of inflammatory cells. This induction was fully dependent on the TNF signaling cascade, because it was not observed in the livers of TNFR1-deficient mice. Furthermore, pretreatment with gliotoxin, an inhibitor of NF-κB activity, abrogated the P. acnes/LPS-induced MIP-3α expression of wild-type mice. These results clearly demonstrate that MIP-3α gene expression is dependent on NF-κB activity in vitro, and indicate that the TNFR1-mediated TNF signaling cascade that leads to NF-κB activation plays an essential role in MIP-3α expression in the murine liver injury model.
Early Response to Rotavirus Infection Involves Massive B Cell Activation
Authors: Blutt Sarah E. , Warfield Kelly L. , Lewis Dorothy E. , Conner Margaret E. 
Published: April 2014

Abstract
Rotavirus is an acute enteric pathogen which induces severe diarrhea in infants and children. To determine the immune response to rotavirus in vivo, we used a mouse model of rotavirus infection. We observed dramatic increases in the sizes of both Peyer’s patches and mesenteric lymph nodes, but not spleen, between 1 and 6 days after infection with a homologous strain of murine rotavirus, EC wild type. Histological analysis showed large increases in the numbers of lymphocytes in these same tissues in rotavirus-infected mice. Flow cytometric analysis confirmed the increase in numbers of lymphocytes and revealed a large increase in the percentage of activated B, but not T, lymphocytes in both Peyer’s patches and mesenteric lymph nodes of rotavirus-infected mice compared with control mice. Fragment cultures from these tissues established at 3–4 days postinfection contain rotavirus-specific IgM but not IgA Ab. A similar degree of lymphoid hyperplasia and percentage of activated B cells were observed in rotavirus-infected TCR knockout mice. Taken together, our findings show that rotavirus infection, in the context of a normal immune response, induces a large increase in the percentages of activated B cells in the absence of any detectable increase in the percentage of activated T cells, implicating a T cell-independent B cell response as the primary mechanism for initial rotavirus clearance.
CCR3 Is Required for Tissue Eosinophilia and Larval Cytotoxicity After Infection withTrichinella spiralis
Authors: Gurish Michael F. , Humbles Alison , Tao Hong , Finkelstein Stella , Boyce Joshua A. , Gerard Craig , Friend Daniel S. , Austen K. Frank 
Published: April 2014

AbstractThe CCR3 binds at least seven different CC chemokines and is expressed on eosinophils, mast cells (MC), and a subset of Th cells (Th2) that generate cytokines implicated in mucosal immune responses. Using mice with a targeted disruption of CCR3 (CCR3−/−) and their +/+ littermates, we investigated the role of CCR3 in the amplification of tissue eosinophilia and MC hyperplasia in the mouse after infection with Trichinella spiralis. In CCR3−/− mice, eosinophils are not recruited to the jejunal mucosa after infection and are not present in the skeletal muscle adjacent to encysting larvae. In addition, the number of cysts in the skeletal muscle is increased and the frequency of encysted larvae exhibiting necrosis is reduced. The CCR3−/− mice exhibit the expected MC hyperplasia in the jejunum and caecum and reject the adult worms from the small intestine at a normal rate. This study is consistent with distinct functions for MC (adult worm expulsion) and eosinophils (toxicity to larvae) in immunity to a helminth, T. spiralis, and defines the essential requirement for CCR3 in eosinophil, but not MC recruitment to tissues.
Multiple Mechanisms Compensate to Enhance Tumor-Protective CD8+ T Cell Response in the Long-Term Despite Poor CD8+ T Cell Priming Initially: Comparison Between an Acute Versus a Chronic Intracellular Bacterium Expressing a Model Antigen
Authors: Dudani Renu , Chapdelaine Yvan , Faassen Henk van , Smith Dean K. , Shen Hao , Krishnan Lakshmi , Sad Subash 
Published: April 2014

AbstractWe evaluated CD8+ T cell responses against the dominant CTL epitope, OVA257–264, expressed by an acute (Listeria monocytogenes (LM) OVA) vs a chronic pathogen (Mycobacterium bovis bacillus Calmette-Guérin (BCG) OVA) to reveal the influence on CD8+ T cell memory and consequent protection against a challenge with OVA-expressing tumor cells. Infection with lower doses of both pathogens resulted in stronger bacterial growth but weaker T cell memory indicating that memory correlates with pathogen dose but not with bacterial expansion. The CD8+ T cell response induced by LM-OVA was helper T cell-independent and was characterized by a rapid effector response followed by a rapid, but massive, attrition. In contrast, BCG-OVA induced a delayed and weak response that was compensated for by a longer effector phase and reduced attrition. This response was partly dependent on CD4+ T cells. CD8+ T cell response induced by BCG-OVA, but not LM-OVA, was highly dependent on pathogen persistence to compensate for the weak initial CD8+ T cell priming. Despite a stronger initial T cell response with LM-OVA, BCG-OVA provided more effective tumor (B16OVA) control at both local and distal sites due to the induction of a persistently activated acquired, and a more potent innate, immunity.
Prothrombin Kringle-2 Activates Cultured Rat Brain Microglia
Authors: Ryu Jooyoung , Min Kyoung-jin , Rhim Tai Youn , Kim Tae Hyong , Pyo Hankyoung , Jin Byungkwan , Kim Seung-Up , Jou Ilo , Kim Soung Soo , Joe Eun-hye 
Published: April 2014

Abstract
Microglia, the major immune effector cells in the CNS, become activated when the brain suffers injury. In this study, we observed that prothrombin, a zymogen of thrombin, induced NO release and mRNA expression of inducible NO synthase, IL-1β, and TNF-α in rat brain microglia. The effect of prothrombin was independent of the protease activity of thrombin since hirudin, a specific inhibitor of thrombin, did not inhibit prothrombin-induced NO release. Furthermore, factor Xa enhanced the effect of prothrombin on microglial NO release. Kringle-2, a domain of prothrombin distinct from thrombin, mimicked the effect of prothrombin in inducing NO release and mRNA expression of inducible NO synthase, IL-1β, and TNF-α. Prothrombin and kringle-2 both triggered the same intracellular signaling pathways. They both activated mitogen-activated protein kinases and NF-κB in a similar pattern. NO release stimulated by either was similarly reduced by inhibitors of the extracellular signal-regulated kinase pathway (PD98059), p38 (SB203580), NF-κB (N-acetylcysteine), protein kinase C (Go6976, bisindolylmaleimide, and Ro31-8220), and phospholipase C (D609 and U73122). These results suggest that prothrombin can activate microglia, and that, in addition to thrombin, kringle-2 is a domain of prothrombin independently capable of activating microglia.
HER-2/neuand hTERT Cryptic Epitopes as Novel Targets for Broad Spectrum Tumor Immunotherapy
Authors: Scardino Antonio , Gross David-Alexandre , Alves Pedro , Schultze Joachim L. , Graff-Dubois Stéphanie , Faure Olivier , Tourdot Sophie , Chouaib Salem , Nadler Lee M. , Lemonnier François A. , Vonderheide Robert H. , Cardoso Angelo A. , Kosmatopoulos Kostas 
Published: April 2014

AbstractTolerance to tumor-nonmutated self proteins represents a major obstacle for successful cancer immunotherapy. Since this tolerance primarily concerns dominant epitopes, we hypothesized that targeting cryptic epitopes that have a low affinity for HLA could be an efficient strategy to breach the tolerance to tumor Ags. Using the P1Y heteroclitic peptide approach, we identified low affinity cryptic HLA-A*0201-restricted epitopes derived from two widely expressed tumor Ags, HER-2/neu and hTERT. The P1Y variants of four HER-2/neu (neu391, neu402, neu466, neu650)- and two hTERT (hTERT572 and hTERT988)-derived low affinity peptides exhibited strong affinity for HLA-A*0201 and stimulated specific CTL from healthy donor PBMCs. These CTL specifically recognized HER-2/neu- and hTERT-expressing tumor cells of various histological origins. In vivo studies showed that HLA-A*0201 transgenic HHD mice vaccinated with the P1Y variant peptides generated CTL that specifically lysed Ag-expressing tumor cells, thus recognizing the cognate endogenous Ags. These results suggest that heteroclitic variants of low affinity, cryptic epitopes of widely expressed tumor Ags may serve as valid tools for tumor immunotherapy.
Functional Heterogeneity of Vaccine-Induced CD8+ T Cells
Authors: Monsurrò Vladia , Nagorsen Dirk , Wang Ena , Provenzano Maurizio , Dudley Mark E. , Rosenberg Steven A. , Marincola Francesco M. 
Published: April 2014

AbstractThe functional status of circulating vaccine-induced, tumor-specific T cells has been questioned to explain their paradoxical inability to inhibit tumor growth. We enumerated with HLA-A*0201/peptide tetramers (tHLA) vaccine-elicited CD8+ T cell precursor frequency among PBMC in 13 patients with melanoma undergoing vaccination with the HLA-A*0201-associated gp100:209–217(210 M) epitope. T cell precursor frequency increased from undetectable to 12,400 ± 3,600 × 106 CD8+ T cells after vaccination and appeared heterogeneous according to previously described functional subtypes: CD45RA+CD27+ (14 ± 2.6% of tHLA-staining T cells), naive; CD45RA−CD27+ (14 ± 3.2%), memory; CD45RA+CD27− (43 ± 6%), effector; and CD45RA−CD27− (30 ± 4.1%), memory/effector. The majority of tHLA+CD8+ T cells displayed an effector, CD27− phenotype (73%). However, few expressed perforin (17%). Epitope-specific in vitro stimulation (IVS) followed by 10-day expansion in IL-2 reversed this phenotype by increasing the number of perforin+ (84 ± 3.6%; by paired t test, p &lt; 0.001) and CD27+ (from 28 to 67%; by paired t test, p = 0.01) tHLA+ T cells. This conversion probably represented a change in the functional status of tHLA+ T cells rather than a preferential expansion of a CD27+ (naive and/or memory) PBMC, because it was reproduced after IVS of a T cell clone bearing a classic effector phenotype (CD45RA+CD27−). These findings suggest that circulating vaccine-elicited T cells are not as functionally active as inferred by characterization of IVS-induced CTL. In addition, CD45RA/CD27 expression may be more informative about the status of activation of circulating T cells than their status of differentiation.
Humoral Autoimmunity to Basement Membrane Antigens Is Regulated in C57BL/6 and MRL/MpJ Mice Transgenic for Anti-Laminin Ig Receptors
Authors: Rudolph Earl H. , Congdon Kendra L. , Sackey Faustina N. A. , Fitzsimons Muriel M. , Foster Mary H. 
Published: April 2014

AbstractBasement membrane proteins are targeted in organ-limited and systemic autoimmune nephritis, yet little is known about the origin or regulation of immunity to these complex extracellular matrices. We used mice transgenic for a nephrotropic systemic lupus erythematosus (SLE) Ig H chain to test the hypothesis that humoral immunity to basement membrane is actively regulated. The LamH-Cμ Ig H chain transgene combines with diverse L chains to produce nephrotropic Ig reactive with murine laminin α1. To determine the fate of transgene-bearing B cells in vivo, transgenic mice were outcrossed onto nonautoimmune B6 and SLE-prone MRL backgrounds and exposed to potent mitogen or Ag in adjuvant. In this work we demonstrate that transgenic autoantibodies are absent in serum from M6 and M29 lineage transgenic mice and transgenic B cells hypoproliferate and fail to increase Ig production upon exposure to endotoxin or when subjected to B cell receptor cross-linking. Administration of LPS or immunization with autologous or heterologous laminin, maneuvers that induce nonoverlapping endogenous anti-laminin IgG responses, fails to induce a transgenic anti-laminin response. The marked reduction in splenic B cell number suggests that selected LamH-Cμ H chain and endogenous L chain combinations generate autospecificities that lead to B cell deletion. It thus appears that SLE-like anti-laminin B cells have access to and engage a tolerizing self-Ag in vivo. Failure to induce autoimmunity by global perturbations in immune regulation introduced by the MRL autoimmune background and exposure to potent environmental challenge suggests that humoral immunity to nephritogenic basement membrane epitopes targeted in systemic autoimmunity is tightly regulated.