bluuebunny/crossref_metadata_2025_split huggingface dataset:
CD4+ T Cells Mediate IFN-γ-Independent Control ofMycobacterium tuberculosisInfection Both In Vitro and In Vivo
Authors: Cowley Siobhán C. , Elkins Karen L. 
Published: April 2014

AbstractAlthough IFN-γ is necessary for survival of Mycobacterium tuberculosis infection in people and animal models, it may not be sufficient to clear the infection, and IFN-γ is not a reliable correlate of protection. To determine whether IFN-γ-independent mechanisms of immunity exist, we developed a murine ex vivo culture system that directly evaluates the ability of splenic or lung lymphocytes to control the growth of M. tuberculosis within infected macrophages, and that models in vivo immunity to tuberculosis. Surprisingly, CD4+ T cells controlled &gt;90% of intracellular M. tuberculosis growth in the complete absence of IFN-γ stimulation of macrophages, via a NO-dependent mechanism. Furthermore, bacillus Calmette-Guerin-vaccinated IFN-γ-deficient mice exhibited significant protection against M. tuberculosis challenge that was lost upon depletion of CD4+ T cells. These findings demonstrate that CD4+ T cells possess IFN-γ-independent mechanisms that can limit the growth of an intracellular pathogen and are dominant in secondary responses to M. tuberculosis.
IL-10 Mediates Suppression of the CD8 T Cell IFN-γ Response to a Novel Viral Epitope in a Primed Host
Authors: Liu Xiao Song , Xu Yan , Hardy Lani , Khammanivong Vithagna , Zhao Weiming , Fernando Germain J. P. , Leggatt Graham R. , Frazer Ian H. 
Published: April 2014

Abstract
Priming to Ag can inhibit subsequent induction of an immune response to a new epitope incorporated into that Ag, a phenomenon referred to as original antigenic sin. In this study, we show that prior immunity to a virus capsid can inhibit subsequent induction of the IFN-γ effector T cell response to a novel CD8-restricted antigenic epitope associated with the virus capsid. Inhibition does not involve Ab to the virus capsid, as it is observed in animals lacking B cells. CD8-restricted virus-specific T cell responses are not required, as priming to virus without CTL induction is associated with inhibition. However, IL-10−/− mice, in contrast to IL-10+/+ mice, generate CD8 T cell and Ab responses to novel epitopes incorporated into a virus capsid, even when priming to the capsid has resulted in high titer Ab to the capsid. Furthermore, capsid-primed mice, unable to mount a response to a novel epitope in the capsid protein, are nevertheless able to respond to the same novel epitope delivered independently of the capsid. Thus, inhibition of responsiveness to a novel epitope in a virus-primed animal is a consequence of secretion of IL-10 in response to presented Ag, which inhibits local generation of new CD8 IFN-γ-secreting effector T cells. Induction of virus- or tumor Ag-specific CD8 effector T cells in the partially Ag-primed host may thus be facilitated by local neutralization of IL-10.
Complement Regulatory Protein C1 Inhibitor Binds to Selectins and Interferes with Endothelial-Leukocyte Adhesion
Authors: Cai Shenghe , Davis Alvin E. 
Published: April 2014

AbstractC1 inhibitor (C1INH), a member of the serine proteinase inhibitor (serpin) family, is an inhibitor of proteases in the complement system, the contact system of kinin generation, and the intrinsic coagulation pathway. It is the most heavily glycosylated plasma protein, containing 13 definitively identified glycosylation sites as well as an additional 7 potential glycosylation sites. C1INH consists of two distinct domains: a serpin domain and an amino-terminal domain. The serpin domain retains all the protease-inhibitory function, while the amino-terminal domain bears most of the glycosylation sites. The present studies test the hypothesis that plasma C1INH bears sialyl Lewisx-related moieties and therefore binds to selectin adhesion molecules. We demonstrated that plasma C1INH does express sialyl Lewisx-related moieties on its N-glycan as detected using mAb HECA-452 and CSLEX1. The data also show that plasma C1INH can bind to P- and E-selectins by FACS and immunoprecipitation experiments. In a tissue culture model of endothelial-leukocyte adhesion, C1INH showed inhibition in a dose-dependent manner. Significant inhibition (&gt;50%) was achieved at a concentration of 250 μg/ml or higher. This discovery may suggest that C1INH plays a role in the endothelial-leukocyte interaction during inflammation. It may also provide another example of the multifaceted anti-inflammatory effects of C1INH in various animal models and human diseases.
Blockade of Vascular Endothelial Growth Factor Receptor I (VEGF-RI), but not VEGF-RII, Suppresses Joint Destruction in the K/BxN Model of Rheumatoid Arthritis
Authors: De Bandt Michel , Ben Mahdi Meriem H. , Ollivier Véronique , Grossin Maggy , Dupuis Magali , Gaudry Murielle , Bohlen Peter , Lipson Kenneth E. , Rice Audie , Wu Yan , Gougerot-Pocidalo Marie-Anne , Pasquier Catherine 
Published: April 2014

Abstract
It was recently shown that vascular endothelial growth factor (VEGF), a growth factor for endothelial cells, plays a pivotal role in rheumatoid arthritis. VEGF binds to specific receptors, known as VEGF-RI and VEGF-RII. We assessed the physical and histological effects of selective blockade of VEGF and its receptors in transgenic K/BxN mice, a model of rheumatoid arthritis very close to the human disease. Mice were treated with anti-mouse VEGF Ab, anti-mouse VEGF-RI and -RII Abs, and an inhibitor of VEGF-RI tyrosine kinase. Disease activity was monitored using clinical indexes and by histological examination. We found that synovial cells from arthritic joints express VEGF, VEGF-RI, and VEGF-RII. Treatment with anti-VEGF-RI strongly attenuated the disease throughout the study period, while anti-VEGF only transiently delayed disease onset. Treatment with anti-VEGF-RII had no effect. Anti-VEGF-RI reduced the intensity of clinical manifestations and, based on qualitative and semiquantitative histological analyses, prevented joint damage. Treatment with a VEGF-RI tyrosine kinase inhibitor almost abolished the disease. These results show that VEGF is a key factor in pannus development, acting through the VEGF-RI pathway. The observation that in vivo administration of specific inhibitors targeting the VEGF-RI pathway suppressed arthritis and prevented bone destruction opens up new possibilities for the treatment of rheumatoid arthritis.
Expression, Localization, and Functional Activity of TL1A, a Novel Th1-Polarizing Cytokine in Inflammatory Bowel Disease
Authors: Bamias Giorgos , Martin Charles , Marini Marco , Hoang Sharon , Mishina Margarita , Ross William G. , Sachedina Muhammadreza A. , Friel Charles M. , Mize James , Bickston Stephen J. , Pizarro Theresa T. , Wei Ping , Cominelli Fabio 
Published: April 2014

Abstract
TL1A is a novel TNF-like factor that acts as a costimulator of IFN-γ secretion through binding to the death domain-containing receptor, DR3. The aim of this study was to test the hypothesis that TL1A may play an important role in inflammatory bowel disease (IBD) by functioning as a Th1-polarizing cytokine. The expression, cellular localization, and functional activity of TL1A and DR3 were studied in intestinal tissue specimens as well as isolated lamina propria mononuclear cells from IBD patients and controls. TL1A mRNA and protein expression was up-regulated in IBD, particularly in involved areas of Crohn’s disease (CD; p &lt; 0.03 vs control). TL1A production was localized to the intestinal lamina propria in macrophages and CD4+ and CD8+ lymphocytes from CD patients as well as in plasma cells from ulcerative colitis patients. The amount of TL1A protein and the number of TL1A-positive cells correlated with the severity of inflammation, most significantly in CD. Increased numbers of immunoreactive DR3-positive T lymphocytes were detected in the intestinal lamina propria from IBD patients. Addition of recombinant human TL1A to cultures of PHA-stimulated lamina propria mononuclear from CD patients significantly augmented IFN-γ production by 4-fold, whereas a minimal effect was observed in control patients. Our study provides evidence for the first time that the novel cytokine TL1A may play an important role in a Th1-mediated disease such as CD.
An Immunomodulatory GpG Oligonucleotide for the Treatment of Autoimmunity via the Innate and Adaptive Immune Systems
Authors: Ho Peggy P. , Fontoura Paulo , Ruiz Pedro J. , Steinman Lawrence , Garren Hideki 
Published: April 2014

Abstract
Bacterial DNA and immunostimulatory CpG oligodeoxynucleotides (ODNs) activate the innate immune system to produce proinflammatory cytokines. Shown to be potent Th1-like adjuvants, stimulatory CpG motifs are currently used as effective therapeutic vaccines for various animal models of infectious diseases, tumors, allergies, and autoimmune diseases. In this study, we show that the application of an immunomodulatory GpG ODN, with a single base switch from CpG to GpG, can effectively inhibit the activation of Th1 T cells associated with autoimmune disease. Moreover, this immunomodulatory GpG ODN suppresses the severity of experimental autoimmune encephalomyelitis in mice, a prototypic Th1-mediated animal disease model for multiple sclerosis.
Analysis of Gene Expression and Ig Transcription in PU.1/Spi-B-Deficient Progenitor B Cell Lines
Authors: Schweitzer Brock L. , DeKoter Rodney P. 
Published: April 2014

AbstractA number of presumptive target genes for the Ets-family transcription factor PU.1 have been identified in the B cell lineage. However, the precise function of PU.1 in B cells has not been studied because targeted null mutation of the PU.1 gene results in a block to lymphomyeloid development at an early developmental stage. In this study, we take advantage of recently developed PU.1−/−Spi-B−/− IL-7 and stromal cell-dependent progenitor B (pro-B) cell lines to analyze the function of PU.1 and Spi-B in B cell development. We show that contrary to previously published expectations, PU.1 and/or Spi-B are not required for Ig H chain (IgH) gene transcription in pro-B cells. In fact, PU.1−/−Spi-B−/− pro-B cells have increased levels of IgH transcription compared with wild-type pro-B cells. In addition, high levels of Igκ transcription are induced after IL-7 withdrawal of wild-type or PU.1−/−Spi-B−/− pro-B cells. In contrast, we found that Igλ transcription is reduced in PU.1−/−Spi-B−/− pro-B cells relative to wild-type pro-B cells after IL-7 withdrawal. These results suggest that Igλ, but not IgH or Igκ, transcription, is dependent on PU.1 and/or Spi-B. The PU.1−/−Spi-B−/− pro-B cells have other phenotypic changes relative to wild-type pro-B cells including increased proliferation, increased CD25 expression, decreased c-Kit expression, and decreased RAG-1 expression. Taken together, our observations suggest that reduction of PU.1 and/or Spi-B activity in pro-B cells promotes their differentiation to a stage intermediate between late pro-B cells and large pre-B cells.
Fully Functional HLA B27-Restricted CD4+ as well as CD8+ T Cell Responses in TCR Transgenic Mice
Authors: Roddis Matthew , Carter Robert W. , Sun Mei-Yi , Weissensteiner Thomas , McMichael Andrew J. , Bowness Paul , Bodmer Helen C. 
Published: April 2014

Abstract
The strong association of HLA B27 with spondyloarthropathies contrasts strikingly with most autoimmune diseases, which are HLA class II associated and thought to be mediated by CD4+ T lymphocytes. By introducing a human-derived HLA B27-restricted TCR into HLA B27 transgenic mice, we have obtained a functional TCR transgenic model, GRb, dependent on HLA B27 for response. Surprisingly, HLA B27 supported CD4+ as well as CD8+ T cell responses in vivo and in vitro. Further, HLA B27-restriced CD4+ T cells were capable of differentiation into a range of Th1 and Th2 T cell subsets with normal patterns of cytokine expression. The transgenic T cells were also able to enhance clearance of recombinant vaccinia virus containing influenza nucleoprotein in vivo. This is the first description of a human HLA class I-restricted TCR transgenic line. The existence of CD4+ MHC class I-restricted T cells has significant implications for immune regulation in autoimmunity and, in particular, in HLA B27-associated arthritis. We believe that this model provides a novel system for the study of unusual T cell behavior in vivo.
Melanoma-Reactive Class I-Restricted Cytotoxic T Cell Clones Are Stimulated by Dendritic Cells Loaded with Synthetic Peptides, but Fail to Respond to Dendritic Cells Pulsed with Melanoma-Derived Heat Shock Proteins In Vitro
Authors: Fleischer Kristina , Schmidt Burkhard , Kastenmüller Wolfgang , Busch Dirk H. , Drexler Ingo , Sutter Gerd , Heike Michael , Peschel Christian , Bernhard Helga 
Published: April 2014

Abstract
Immunization with heat shock proteins (hsp) isolated from cancer cells has been shown to induce a protective antitumor response. The mechanism of hsp-dependent cellular immunity has been attributed to a variety of immunological activities mediated by hsp. Hsp have been shown to bind antigenic peptides, trim the bound peptides by intrinsic enzymatic activity, improve endocytosis of the chaperoned peptides by APCs, and enhance the ability of APCs to stimulate peptide-specific T cells. We have investigated the potential capacity of hsp70 and gp96 to function as a mediator for Ag-specific CTL stimulation in an in vitro model for human melanoma. Repetitive stimulation of PBLs by autologous DCs loaded with melanoma-derived hsp did not increase the frequency of T cells directed against immunodominant peptides of melanoma-associated Ags Melan-A and tyrosinase. In contrast, repeated T cell stimulation with peptide-pulsed DCs enhanced the number of peptide-specific T cells, allowing HLA/peptide multimer-guided T cell cloning. We succeeded in demonstrating that the established HLA-A2-restricted CTL clones recognized HLA-A2+ APCs exogenously loaded with the respective melanoma peptide as well as melanoma cells processing and presenting these peptides in the context of HLA-A2. We were not able to show that these melanoma-reactive CTL clones were stimulated by autologous dendritic cells pulsed with melanoma-derived hsp. These results are discussed with respect to various models for proving the role of hsp in T cell stimulation and to recent findings that part of the immunological antitumor activities reported for hsp are independent of the chaperoned peptides.
CD1-Dependent Regulation of Chronic Central Nervous System Inflammation in Experimental Autoimmune Encephalomyelitis
Authors: Teige Anna , Teige Ingrid , Lavasani Shahram , Bockermann Robert , Mondoc Emma , Holmdahl Rikard , Issazadeh-Navikas Shohreh 
Published: April 2014

Abstract
The existence of T cells restricted for the MHC I-like molecule CD1 is well established, but the function of these cells is still obscure; one implication is that CD1-dependent T cells regulate autoimmunity. In this study, we investigate their role in experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis, using CD1-deficient mice on a C57BL/6 background. We show that CD1−/− mice develop a clinically more severe and chronic EAE compared with CD1+/+ C57BL/6 mice, which was histopathologically confirmed with increased demyelination and CNS infiltration in CD1−/− mice. Autoantigen rechallenge in vitro revealed similar T cell proliferation in CD1+/+ and CD1−/− mice but an amplified cytokine response in CD1−/− mice as measured by both the Th1 cytokine IFN-γ and the Th2 cytokine IL-4. Investigation of cytokine production at the site of inflammation showed a CNS influx of TGF-β1-producing cells early in the disease in CD1+/+ mice, which was absent in the CD1−/− mice. Passive transfer of EAE using an autoreactive T cell line induced equivalent disease in both groups, which suggested additional requirements for activation of the CD1-dependent regulatory pathway(s). When immunized with CFA before T cell transfer, the CD1−/− mice again developed an augmented EAE compared with CD1+/+ mice. We suggest that CD1 exerts its function during CFA-mediated activation, regulating development of EAE both through enhancing TGF-β1 production and through limiting autoreactive T cell activation, but not necessarily via effects on the Th1/Th2 balance.
Regulation of CD103 Expression by CD8+ T Cells Responding to Renal Allografts
Authors: Wang Donghua , Yuan Rongwen , Feng Ye , El-Asady Riham , Farber Donna L. , Gress Ronald E. , Lucas Philip J. , Hadley Gregg A. 
Published: April 2014

AbstractCD103 is an integrin with specificity for the epithelial cell-specific ligand, E-cadherin. Recent studies indicate that CD103 expression endows peripheral CD8 cells with a unique capacity to access the epithelial compartments of organ allografts. In the present study we used a nonvascularized mouse renal allograft model to 1) define the mechanisms regulating CD103 expression by graft-infiltrating CD8 effector populations, and 2) identify the cellular compartments in which this occurs. We report that CD8 cells responding to donor alloantigens in host lymphoid compartments do not initially express CD103, but dramatically up-regulate CD103 expression to high levels subsequent to migration to the graft site. CD103+CD8+ cells that infiltrated renal allografts exhibited a classic effector phenotype and were selectively localized to the graft site. CD8 cells expressing low levels of CD103 were also present in lymphoid compartments, but three-color analyses revealed that these are almost exclusively of naive phenotype. Adoptive transfer studies using TCR-transgenic CD8 cells demonstrated that donor-specific CD8 cells rapidly and uniformly up-regulate CD103 expression following entry into the graft site. Donor-specific CD8 cells expressing a dominant negative TGF-β receptor were highly deficient in CD103 expression following migration to the graft, thereby implicating TGF-β activity as a dominant controlling factor. The relevance of these data to conventional (vascularized) renal transplantation is confirmed. These data support a model in which TGF-β activity present locally at the graft site plays a critical role in regulating CD103 expression, and hence the epitheliotropism, of CD8 effector populations that infiltrate renal allografts.
Superantigen Stimulation Reveals the Contribution of Lck to Negative Regulation of T Cell Activation
Authors: Criado Gabriel , Madrenas Joaquín 
Published: April 2014

AbstractThe conventional paradigm of T cell activation through the TCR states that Lck plays a critical activating role in this signaling process. However, the T cell response to bacterial superantigens does not require Lck. In this study we report that not only is Lck dispensable for T cell activation by superantigens, but it actively inhibits this signaling pathway. Disruption of Lck function, either by repression of Lck gene expression or by selective pharmacologic inhibitors of Lck, led to increased IL-2 production in response to superantigen stimulation. This negative regulatory effect of Lck on superantigen-induced T cell responses required the kinase activity of Lck and correlated with early TCR signaling, but was independent of immunological synapse formation and TCR internalization. Our data demonstrate that the multistage role of Lck in T cell signaling includes the activation of a negative regulatory pathway of T cell activation.
Two Distinct Waves of Membrane-Proximal B Cell Antigen Receptor Signaling Differentially Regulated by Src Homology 2-Containing Inositol Polyphosphate 5-Phosphatase
Authors: Krahn Allyson K. , Ma Kewei , Hou Sen , Duronio Vincent , Marshall Aaron J. 
Published: April 2014

Abstract
The phosphatidylinositol 3-kinase (PI3K) pathway plays a critical role in B cell activation and differentiation. Recruitment of pleckstrin homology (PH) domain-containing signal transduction proteins to the plasma membrane through binding to 3-phosphoinositide second messengers represents a major effector mechanism for PI3Ks. We have found that the PH domains of Bam32 and tandem PH domain-containing protein 2 (TAPP2) specify a temporally distinct wave of membrane recruitment compared with that of Bruton’s tyrosine kinase (Btk), with recruitment of these two adaptors representing a later stage of the response. In this study we provide direct evidence that PH domain-dependent recruitment of Btk to the membrane is blocked by coligation of the inhibitory receptor FcγRII in human B lymphoma cells. In contrast, recruitment specified by the Bam32 or TAPP2 PH domains is completely insensitive to FcγRII inhibition. This differential regulation can be accounted for by Src homology 2-containing inositol polyphosphate 5-phosphatase (SHIP) activity alone, as expression of membrane-targeted SHIP completely abrogated Btk recruitment, but had no inhibitory effect on Bam32 or TAPP2 recruitment. Strikingly, kinetic analysis revealed that membrane recruitment of Bam32 and TAPP2 is actually more rapid under “inhibitory” signaling conditions. Analysis of 3-phosphoinositide generation under activating and inhibitory signaling conditions indicated that recruitment of Bam32 and TAPP2 is inversely correlated with the SHIP substrate/product ratio (phosphatidylinositol 3,4,5-trisphosphate/phosphatidylinositol 3,4-bisphosphate). Overexpression of TAPP2 in B cells led to an increase in the sustained phase of the calcium response and increased NF-AT-dependent transcriptional activation after B cell Ag receptor ligation. Together, these results suggest that Bam32 and TAPP2 adaptors define a novel group of SHIP-activated targets of PI3K that regulate B cell Ag receptor signaling.
Herpes Simplex Virus-Specific CD8+ T Cells Can Clear Established Lytic Infections from Skin and Nerves and Can Partially Limit the Early Spread of Virus after Cutaneous Inoculation
Authors: van Lint Allison , Ayers Margaret , Brooks Andrew G. , Coles Richard M. , Heath William R. , Carbone Francis R. 
Published: April 2014

Abstract
HSV infects skin or mucosal epithelium as well as entering the sensory nerves and ganglia. We have used TCR-transgenic T cells specific for the immunodominant class I-restricted determinant from HSV glycoprotein B (gB) combined with a flank zosteriform model of infection to examine the ability of CD8+ T cells to deal with infection. During the course of zosteriform disease, virus rapidly spreads from the primary inoculation site in the skin to sensory dorsal root ganglia and subsequently reappears in the distal flank. Virus begins to be cleared from all sites about 5 days after infection when gB-specific CD8+ T cells first appear within infected tissues. Although activated gB-specific effectors can partially limit virus egress from the skin, they do so only at the earliest times after infection and are ineffective at halting the progression of zosteriform disease once virus has left the inoculation site. In contrast, these same T cells can completely clear ongoing lytic replication if transferred into infected immunocompromised RAG-1−/− mice. Therefore, we propose that the role of CD8+ T cells during the normal course of disease is to clear replicating virus after infection is well established rather than limit the initial spread of HSV from the primary site of inoculation.