bluuebunny/crossref_metadata_2025_split huggingface dataset:
Aspirin and Salicylates Inhibit the IL-4- and IL-13-Induced Activation of STAT6
Authors: Perez-G. Moises , Melo Marco , Keegan Achsah D. , Zamorano Jose 
Published: April 2014

AbstractAllergic diseases, including asthma, represent a major threat to human health. Over the three last decades, their incidence has risen in western countries. Aspirin treatment has been shown to improve allergic diseases, especially asthma, and the decreased use of aspirin has been hypothesized to contribute to the increase in childhood asthma. Because salicylate compounds suppress a number of enzymatic activities, and signaling through IL-4R participates in the development of allergic responses, we tested the effect of salicylates on IL-4 signal transduction. We found that treatment of cell lines and primary cells with aspirin and salicylates, but not acetaminophen, inhibited the activation of STAT6 by IL-4 and IL-13. This effect correlated with the inhibition of IL-4-induced CD23 expression. Although salicylates inhibited the in vivo activation of Janus kinases, their kinase activity was not affected in vitro by salicylates, suggesting that other kinases were involved in IL-4-induced STAT6 activation. Furthermore, we found that an Src kinase was involved in STAT6 activation because 1) Src kinase activity was induced by IL-4, 2) Src kinase activity, but not Janus kinase, was inhibited by salicylates in vitro, 3) cells expressing viral Src had constitutive STAT6 phosphorylation, and 4) cells lacking Src showed low STAT6 phosphorylation in response to IL-4. Because STAT6 activation by IL-4 and IL-13 participates in the development of allergic diseases, our results provide a mechanism to explain the beneficial effects of aspirin and salicylate treatment of these diseases.
Administration of Agonistic Anti-4-1BB Monoclonal Antibody Leads to the Amelioration of Experimental Autoimmune Encephalomyelitis
Authors: Sun Yonglian , Lin Xiaoqi , Chen Helen M. , Wu Qiang , Subudhi Sumit K. , Chen Lieping , Fu Yang-Xin 
Published: April 2014

Abstract4-1BB, a member of the TNFR superfamily, is a costimulatory receptor primarily expressed on activated T cells. It has been shown that the administration of agonistic anti-4-1BB Abs enhances tumor immunity and allogenic immune responses. Paradoxically, we found that the administration of an agonistic anti-4-1BB mAb (2A) dramatically reduced the incidence and severity of experimental autoimmune encephalomyelitis (EAE). Adoptive transfer of T cells from such treated mice failed to induce EAE, whereas anti-4-1BB treatment following adoptive transfer of encephalitogenic T cells did not prevent EAE pathogenesis. These results suggest that anti-4-1BB treatment during the induction phase inhibits autoreactive T cell immune responses rather than preventing T cell trafficking into the CNS. This was substantiated by the observations that draining lymph node cells from anti-4-1BB-treated mice failed to respond to Ag stimulation in vitro. In addition, we found that such treatment initially promotes the activation and proliferation of Ag-specific CD4+ T cells but subsequently increases their probability of undergoing activation-induced cell death, thereby inhibiting effector T cell responses. More importantly, 2A treatment also inhibits the relapse of EAE in a clinically relevant murine model of multiple sclerosis. This study indicates that the agonistic Ab against 4-1BB can potentially be used as a novel immunotherapeutic agent for treating autoimmune diseases.
In Situ β Cell Death Promotes Priming of Diabetogenic CD8 T Lymphocytes
Authors: Zhang Yiqun , O’Brien Bronwyn , Trudeau Jacqueline , Tan Rusung , Santamaria Pere , Dutz Jan P. 
Published: April 2014

AbstractCTLs are important mediators of pancreatic β cell destruction in the nonobese diabetic mouse model of type 1 diabetes. Cross-presentation of Ag is one means of priming CTLs. The death of Ag-bearing cells has been implicated in facilitating this mode of priming. The role of β cell death in facilitating the onset of spontaneous autoimmune diabetes is unknown. Here, we used an adoptive transfer system to determine the time course of islet-derived Ag presentation to naive β cell-specific CD8 T cells in nonobese diabetic mice and to test the hypothesis that β cell death enhances the presentation of β cell autoantigen. We have determined that β cell death enhances autoantigen presentation. Priming of diabetogenic CD8 T cells in the pancreatic lymph nodes was negligible before 4 wk, progressively increased until 8 wk of age, and was not influenced by gender. Administration of multiple low doses of the β cell toxin streptozotocin augmented in situ β cell apoptosis and accelerated the onset and magnitude of autoantigen presentation to naive CD8 T cells. Increasing doses of streptozotocin resulted in both increased pancreatic β cell death and significantly enhanced T cell priming. These results indicate that in situ β cell death facilitates autoantigen-specific CD8 T cell priming and can contribute to both the initiation and the ongoing amplification of an autoimmune response.
Selective Decrease in Circulating Vα24+Vβ11+ NKT Cells During HIV Type 1 Infection
Authors: van der Vliet Hans J. J. , von Blomberg B. Mary E. , Hazenberg Mette D. , Nishi Nobusuke , Otto Sigrid A. , van Benthem Birgit H. , Prins Maria , Claessen Frans A. , van den Eertwegh Alfons J. M. , Giaccone Giuseppe , Miedema Frank , Scheper Rik J. , Pinedo Herbert M. 
Published: April 2014

AbstractCD1d-restricted NKT cells express an invariant TCR and have been demonstrated to play an important regulatory role in a variety of immune responses. Invariant NKT cells down-regulate autoimmune responses by production of type 2 cytokines and can initiate antitumor and antimicrobial immune responses by production of type 1 cytokines. Although defects in the (invariant) Vα24+Vβ11+ NKT cell population have been observed in patients with cancer and autoimmune diseases, little is known regarding the protective role of Vα24+Vβ11+ NKT cells in human infectious disease. In a cross-sectional study in HIV-1-infected individuals, we found circulating numbers of Vα24+Vβ11+ NKT cells to be reduced, independent of CD4+ T cell counts, CD4:CD8 ratios, and viral load. Because a small minority of Vα24+Vβ11+ NKT cells of healthy donors expressed HIV-1 (co)receptors and the vast majority of Vα24+Vβ11+ NKT cells in HIV-1-infected individuals expressed the Fas receptor, the depletion was more likely due to Fas-mediated apoptosis than to preferential infection of Vα24+Vβ11+ NKT cells by HIV-1. A longitudinal cohort study, in which patients were analyzed before seroconversion and 1 and 5 years after seroconversion, demonstrated that a large proportion of the depletion occurred within the first year postseroconversion. In this longitudinal study no evidence was found to support an important role of Vα24+Vβ11+ NKT cells in determining the rate of progression during HIV-1 infection.
Cutting Edge: Compartmentalization of Th1-Like Noninvariant CD1d-Reactive T Cells in Hepatitis C Virus-Infected Liver
Authors: Exley Mark A. , He Qi , Cheng Olivia , Wang Ruo-Jie , Cheney Catherine P. , Balk Steven P. , Koziel Margaret J. 
Published: April 2014

AbstractMurine intrahepatic lymphocytes (IHL) are dominated by invariant TCR α-chain expressing CD1d-reactive NKT cells, which can cause model hepatitis. Invariant NKT (CD56+/−CD161+) and recently identified noninvariant CD1d-reactive T cells rapidly produce large amounts of IL-4 and/or IFN-γ and can regulate Th1/Th2 responses. Human liver contains large numbers of CD56+ NKT cells but few invariant NKT. Compared with matched peripheral blood T cell lines, primary IHL lines from patients with chronic hepatitis C had high levels of CD161 and CD1d reactivity, but the invariant TCR was rare. CD1d-reactive IHL were strikingly Th1 biased. IHL also demonstrated CD1d-specific cytotoxic activity. Hepatocytes and other liver cells express CD1d. These results identify a novel population of human T cells that could contribute to destructive as well as protective immune responses in the liver. CD1d-reactive T cells may have distinct roles in different tissues.
Cutting Edge: Immune Stimulation by Neisserial Porins Is Toll-Like Receptor 2 and MyD88 Dependent
Authors: Massari Paola , Henneke Philipp , Ho Yu , Latz Eicke , Golenbock Douglas T. , Wetzler Lee M. 
Published: April 2014

AbstractThe immunopotentiating activity of neisserial porins, the major outer membrane protein of the pathogenic Neisseria, is mediated by its ability to stimulate B cells and up-regulate the surface expression of B7-2. This ability is dependent on MyD88 and Toll-like receptor (TLR)2 expression, as demonstrated by a lack of a response by B cells from MyD88 or TLR2 knockout mice to the porins. Using previously described TLR2-dependent reporter constructs, these results were confirmed and were shown to be due to induction of NF-κB nuclear translocation. This is the first demonstration of known vaccine adjuvant to stimulate immune cells via TLR2.
Cutting Edge: Tapasin Is Retained in the Endoplasmic Reticulum by Dynamic Clustering and Exclusion from Endoplasmic Reticulum Exit Sites
Authors: Pentcheva Tsvetelina , Spiliotis Elias T. , Edidin Michael 
Published: April 2014

Abstract
Tapasin retains empty or suboptimally loaded MHC class I molecules in the endoplasmic reticulum (ER). However, the molecular mechanism of this process and how tapasin itself is retained in the ER are unknown. These questions were addressed by tagging tapasin with the cyan fluorescent protein or yellow fluorescent protein (YFP) and probing the distribution and mobility of the tagged proteins. YFP-tapasin molecules were functional and could be isolated in association with TAP, as reported for native tapasin. YFP-tapasin was excluded from ER exit sites even after accumulation of secretory cargo due to disrupted anterograde traffic. Almost all tapasin molecules were clustered, and these clusters diffused freely in the ER. Tapasin oligomers appear to be retained by the failure of the export machinery to recognize them as cargo.
Cutting Edge: The Toll Pathway Is Required for Resistance to Gram-Positive Bacterial Infections in Drosophila
Authors: Rutschmann Sophie , Kilinc Ahmet , Ferrandon Dominique 
Published: April 2014

Abstract
In Drosophila, the response against various microorganisms involves different recognition and signaling pathways, as well as distinct antimicrobial effectors. On the one hand, the immune deficiency pathway regulates the expression of antimicrobial peptides that are active against Gram-negative bacteria. On the other hand, the Toll pathway is involved in the defense against filamentous fungi and controls the expression of antifungal peptide genes. The gene coding for the only known peptide with high activity against Gram-positive bacteria, Defensin, is regulated by both pathways. So far, survival experiments to Gram-positive bacteria have been performed with Micrococcus luteus and have failed to reveal the involvement of one or the other pathway in host defense against such infections. In this study, we report that the Toll pathway, but not that of immune deficiency, is required for resistance to other Gram-positive bacteria and that this response does not involve Defensin.
Cutting Edge: A Critical Role for IL-10 in Induction of Nasal Tolerance in Experimental Autoimmune Myocarditis
Authors: Kaya Ziya , Dohmen K. Malte , Wang Yan , Schlichting Jens , Afanasyeva Marina , Leuschner Florian , Rose Noel R. 
Published: April 2014

AbstractAppropriate treatment of autoimmune myocarditis following virus infection remains a major clinical problem. Induction of nasal tolerance may provide a new approach to treatment. However, the exact mechanism of nasal tolerance is unknown. To assess the mechanism of nasal tolerance, we examined the role of IL-10 in the induction and suppression of autoimmune myocarditis. First we showed that blocking IL-10 concurrent with nasal administration of Ag abolished the disease-suppressing effect of nasal tolerization. It also led to increased cardiac myosin-specific IL-1 and TNF-α production. Then we demonstrated that blocking IL-10 during the effector phase increased not only the incidence and severity of disease but also Ag-specific IL-2, IL-4, and TNF-α production as well as cardiac myosin-specific IgG1 and IgG2b production, whereas blocking IL-10 during the induction phase had no effect. This study implicates IL-10 in the induction of nasal tolerance and in limiting inflammation later during the disease process.
Differential SLP-76 Expression and TCR-Mediated Signaling in Effector and Memory CD4 T Cells
Authors: Hussain S. Farzana , Anderson Charles F. , Farber Donna L. 
Published: April 2014

AbstractWe present in this study novel findings on TCR-mediated signaling in naive, effector, and memory CD4 T cells that identify critical biochemical markers to distinguish these subsets. We demonstrate that relative to naive CD4 T cells, memory CD4 T cells exhibit a profound decrease in expression of the linker/adapter molecule SLP-76, while effector T cells express normal to elevated levels of SLP-76. The reduced level of SLP-76 is memory CD4 T cells is coincident with reduced phosphorylation overall, yet the residual SLP-76 couples to a subset of TCR-associated linker molecules, leading to downstream mitogen-activated protein (MAP) kinase activation. By contrast, effector CD4 T cells strongly phosphorylate SLP-76, linker for activation of T cells, and additional Grb2-coupled proteins, exhibit increased associations of SLP-76 to phosphorylated linkers, and hyperphosphorylate downstream Erk1/2 MAP kinases. Our results suggest distinct coupling of signaling intermediates to the TCR in naive, effector, and memory CD4 T cells. Whereas effector CD4 T cells amplify existing TCR signaling events accounting for rapid effector responses, memory T cells engage fewer signaling intermediates to efficiently link TCR triggering directly to downstream MAP kinase activation.
L-Selectin-Dependent Lymphoid Occupancy Is Required to Induce Alloantigen-Specific Tolerance
Authors: Bai Yalai , Liu Jianhua , Wang Yinong , Honig Shaun , Qin Lihui , Boros Peter , Bromberg Jonathan S. 
Published: April 2014

Abstract
Maneuvers that interfere with signals 1, 2, 3, or Ag processing can result in indefinite allograft survival. However, they are not applicable to all tissues, strains, or species, suggesting that there are additional levels of immune regulation. We hypothesized that secondary lymphoid organs are important for interactions among lymphocytes, alloantigen, and immunosuppressants that lead to tolerance. To explore this, cardiac allografts were performed with a tolerogenic immunosuppressive regimen. Concurrent administration of anti-L-selectin (CD62L) Ab, which prevents lymph node homing, prevents indefinite allograft survival and tolerance. Anti-CD62L Ab is not costimulatory, and Fab and F(ab′)2 anti-CD62L have similar activities. Flow cytometry and histologic examination show that Ab shifts T cells away from lymph nodes and into spleen, peripheral blood, and graft. Tolerance is not induced in CD62L−/− mice, and adoptive transfer of CD62L−/−, but not CD62L+/+, T cells prevents tolerization in wild-type recipients. FTY720, an immunosuppressant that promotes chemokine-dependent, but CD62L-independent, lymph node homing, reverses the Ab effect. Blockade of other homing receptors also prevents tolerization. These results indicate that T lymphocytes use CD62L-dependent migration for alloantigen-specific tolerance, and suggest that lymph nodes or other lymphoid tissues are an important site for peripheral tolerization to alloantigen.
Preferential Th1 Immune Response in Invariant Chain-Deficient Mice
Authors: Topilski Ian , Harmelin Alon , Flavell Richard A. , Levo Yoram , Shachar Idit 
Published: April 2014

AbstractMHC class II molecules associate with the invariant chain (Ii) molecule during biosynthesis. Ii facilitates the folding of class II molecules, interferes with their peptide association, and is involved in MHC class II transport. In this study, we have investigated the in vitro and in vivo immune response of Ii-deficient mice (Ii−/−). Our results have demonstrated that CD4+ T cells from Ii−/− mice proliferate normally in vitro after in vivo immunization with protein Ags. However, cytokine secretion profiles of Ag-primed CD4+ T cells from Ii−/− mice differ from CD4+ T cells from wild-type mice. Whereas cells from wild-type mice secrete IFN-γ and IL-4, cells from Ii−/− mice secrete mostly IFN-γ. Moreover, Ii−/− mice exhibit a normal Th1 response in the delayed-type hypersensitivity and trinitrobenzene sulfonic acid colitis models; however, these mice lack an in vivo Th2 response, as demonstrated in the asthma model. Therefore, we suggest that defective Ag presentation in Ii−/− mice leads selectively to a Th1 effector response.
Vascular Endothelial-Junctional Adhesion Molecule (VE-JAM)/JAM 2 Interacts with T, NK, and Dendritic Cells Through JAM 3
Authors: Liang Tony W. , Chiu Henry H. , Gurney Austin , Sidle Aiko , Tumas Daniel B. , Schow Peter , Foster Jessica , Klassen Toni , Dennis Kathryn , DeMarco Richard A. , Pham Thinh , Frantz Gretchen , Fong Sherman 
Published: April 2014

Abstract
Screening expressed sequence tag databases for endothelial-specific homologs to human junctional adhesion molecule (JAM) and A33-Ag, we identified a protein of 298 aa that represents the recently described vascular endothelial-JAM (VE-JAM)/JAM 2. We confirmed VE-JAM/JAM 2 expression to be restricted to the high endothelial venule of tonsil and lymph nodes, and we further expanded the localization to the endothelium of arterioles in and around inflammatory and tumor foci. In our functional characterizations of VE-JAM/JAM 2, we discovered that it can function as an adhesive ligand for the T cell line J45 and can interact with GM-CSF/IL-4-derived peripheral blood dendritic cells, circulating CD56+ NK cells, circulating CD56+CD3+ NK/T cells, and circulating CD56+CD3+CD8+ cytolytic T cells. In the course of our studies, we also isolated and characterized the functional VE-JAM/JAM 2 receptor, which, upon cloning, turned out to be a submitted sequence representing JAM 3 (accession number NP 113658). With these understandings, we have characterized a protein-interacting pair that can be important in the role of T, NK, and dendritic cell trafficking and inflammation.
Quantitative and Qualitative Adjustment of Thymic T Cell Production by Clonal Expansion of Premigrant Thymocytes
Authors: Le Campion Armelle , Lucas Bruno , Dautigny Nicole , Léaument Sandrine , Vasseur Florence , Pénit Claude 
Published: April 2014

AbstractIn normal mice, single-positive thymocytes proliferate before being exported into the peripheral T cell pool. We measured the in vivo proliferation rates of mature thymocytes in several TCR transgenic mice. Different monoclonal TCR transgenic single-positive thymocytes proliferated at different rates in a given MHC context. Conversely, mature thymocytes expressing a given TCR, generated in mice of different MHC haplotypes, also showed different rates of proliferation. In p59fyn-deficient mice, the proliferation rate of mature thymocytes was diminished. Thus, premigrant thymocyte expansion is TCR mediated and depends on TCR affinity for self peptide/MHC ligands. In addition, we show that mature thymocyte expansion is clonotypic, increases the daily thymic T cell output, and modifies the TCR repertoire of newly produced T cells.
Minor Histocompatibility Antigen-Specific MHC-Restricted CD8 T Cell Responses Elicited by Heat Shock Proteins
Authors: Robert Jacques , Gantress Jennifer , Rau Laura , Bell Alisa , Cohen Nicholas 
Published: April 2014

AbstractIn mammals, the heat shock proteins (HSP) gp96 and hsp70 elicit potent specific MHC class I-restricted CD8+ T cell (CTL) response to exogenous peptides they chaperone. We show in this study that in the adult frog Xenopus, a species whose common ancestors with mammals date back 300 million years, both hsp70 and gp96 generate an adaptive specific cellular immune response against chaperoned minor histocompatibility antigenic peptides that effects an accelerated rejection of minor histocompatibility-locus disparate skin grafts in vivo and an MHC-specific CD8+ cytotoxic T cell response in vitro. In naturally class I-deficient but immunocompetent Xenopus larvae, gp96 also generates an antitumor immune response that is independent of chaperoned peptides (i.e., gp96 purified from normal tissue also generates a significant antitumor response); this suggests a prominent contribution of an innate type of response in the absence of MHC class I Ags.
Microbial Compounds Selectively Induce Th1 Cell-Promoting or Th2 Cell-Promoting Dendritic Cells In Vitro with Diverse Th Cell-Polarizing Signals
Authors: de Jong Esther C. , Vieira Pedro L. , Kalinski Pawel , Schuitemaker Joost H. N. , Tanaka Yuetsu , Wierenga Eddy A. , Yazdanbakhsh Maria , Kapsenberg Martien L. 
Published: April 2014

AbstractUpon microbial infection, specific Th1 or Th2 responses develop depending on the type of microbe. Here, we demonstrate that different microbial compounds polarize the maturation of human myeloid dendritic cells (DCs) into stably committed Th1 cell-promoting (DC1) or Th2 cell-promoting (DC2) effector DCs that polarize Th cells via different mechanisms. Protein extract derived from the helminth Schistosoma mansoni induced the development of DC2s that promote the development of Th2 cells via the enhanced expression of OX40 ligand. Likewise, toxin from the extracellular bacterium Vibrio cholerae induced development of DC2s as well, however, via an OX40 ligand-independent, still unknown mechanism. In contrast, toxin from the intracellular bacterium Bordetella pertussis induced the development of DC1s with enhanced IL-12 production, which promotes a Th1 cell development. Poly(I:C) (dsRNA, mimic for virus) induced the development of extremely potent Th1-inducing DC1, surprisingly, without an enhanced IL-12 production. The obtained DC1s and DC2s are genuine effector cells that stably express Th cell-polarizing factors and are unresponsive to further modulation. The data suggest that the molecular basis of Th1/Th2 polarization via DCs is unexpectedly diverse and is adapted to the nature of the microbial compounds.
Repeated Antigen Exposure Is Necessary for the Differentiation, But Not the Initial Proliferation, of Naive CD4+ T Cells
Authors: Bajénoff Marc , Wurtz Olivier , Guerder Sylvie 
Published: April 2014

Abstract
The mechanisms that regulate CD4+ T cells responses in vivo are still poorly understood. We show here that initial Ag stimulation induces in CD4+ T cells a program of proliferation that can develop, for at least seven cycles of division, in the absence of subsequent Ag or cytokine requirement. Thereafter, proliferation stops but can be reinitiated by novel Ag stimulation. This initial Ag stimulation does not however suffice to induce the differentiation of naive CD4+ T cells into effector Th1 cells which requires multiple contacts with Ag-loaded APC. Thus, recurrent exposure to both Ag and polarizing cytokines appears to be essential for the differentiation of IFN-γ-producing cells. Ag and cytokine availability therefore greatly limits the differentiation, but not the initial proliferation, of CD4+ T cells into IFN-γ-producing cells.