bluuebunny/crossref_metadata_2025_split huggingface dataset:
CD40 Ligand Enhances Dengue Viral Infection of Dendritic Cells: A Possible Mechanism for T Cell-Mediated Immunopathology
Authors: Sun Peifang , Celluzzi Christina M. , Marovich Mary , Subramanian Hemavathy , Eller Michael , Widjaja Susana , Palmer Dupeh , Porter Kevin , Sun Wellington , Burgess Timothy 
Published: April 2014

AbstractWe have previously shown that dengue virus (DV) productively infects immature human dendritic cells (DCs) through binding to cell surface DC-specific ICAM-3-grabbing nonintegrin molecules. Infected DCs are apoptotic, refractory to TNF-α stimulation, inhibited from undergoing maturation, and unable to stimulate T cells. In this study, we show that maturation of infected DCs could be restored by a strong stimulus, CD40L. Addition of CD40L significantly reduced apoptosis of DCs, promoted IL-12 production, and greatly elevated the IFN-γ response of T cells, but yet did not restore T cell proliferation in MLR. Increased viral infection of DCs was also observed; however, increased infection did not appear to be mediated by DC-specific ICAM-3-grabbing nonintegrin, but rather was regulated by decreased production of IFN-α and decreased apoptotic death of infected DCs. Because CD40L is highly expressed on activated memory (but not naive) T cells, the observation that CD40L signaling results in enhanced DV infection of DC suggests a possible T cell-dependent mechanism for the immune-mediated enhancement of disease severity associated with some secondary dengue infections.
A Truncated Alternative Spliced Isoform of Human Desmoglein 1 Contains a Specific T Cell Epitope Binding to the Pemphigus Foliaceus-Associated HLA Class II DRβ1*0102 Molecule
Authors: Mouquet Hugo , Farci Sandrine , Joly Pascal , Maillère Bernard , Leblond Jonathan , Drouot Laurent , Leprince Jérôme , Tonon Marie Christine , Loiseau Pascale , Charron Dominique , Tron François , Gilbert Danièle 
Published: April 2014

AbstractDesmogleins (Dsg) are transmembrane glycoproteins of the desmosome that allow a cell-cell adhesion between keratinocytes and comprise four different isoforms (Dsg1 to Dsg4). Two Dsg are targeted by pathogenic autoantibodies produced in the course of autoimmune bullous skin diseases, Dsg1 in pemphigus foliaceus (PF), and Dsg3 and Dsg1 in pemphigus vulgaris. The genetic susceptibility to PF is associated with certain HLA class II alleles, which are thought to participate in disease pathogenesis through their capacity to accommodate autoantigen-derived peptides and present them to autoreactive T cells. So far, a unique isoform of Dsg1 has been described in humans, which includes several immunodominant T cell epitopes. In this study, we describe an alternative transcript of DSG1, which contains a 101-bp insertion corresponding to the 3′ end of DSG1-intron 6 and introducing a stop codon in the nucleotide sequence. This alternative transcript leads to the synthesis of a truncated isoform of Dsg1 expressed in normal human epidermis. This isoform bears a specific peptide sequence that binds to the PF-associated HLA class II DRβ1*0102 molecule as shown in a HLA-DR peptide-binding assay, and induces PF T cell proliferation. These data provide an illustration of an autoantigen encoded by alternative spliced transcript that may participate in the pathogenesis of the disease by bearing PF-associated HLA class II restricted-epitope.
Gene Transfer of Tumor-Reactive TCR Confers Both High Avidity and Tumor Reactivity to Nonreactive Peripheral Blood Mononuclear Cells and Tumor-Infiltrating Lymphocytes
Authors: Johnson Laura A. , Heemskerk Bianca , Powell Daniel J. , Cohen Cyrille J. , Morgan Richard A. , Dudley Mark E. , Robbins Paul F. , Rosenberg Steven A. 
Published: April 2014

AbstractCell-based antitumor immunity is driven by CD8+ cytotoxic T cells bearing TCR that recognize specific tumor-associated peptides bound to class I MHC molecules. Of several cellular proteins involved in T cell:target-cell interaction, the TCR determines specificity of binding; however, the relative amount of its contribution to cellular avidity remains unknown. To study the relationship between TCR affinity and cellular avidity, with the intent of identifying optimal TCR for gene therapy, we derived 24 MART-1:27-35 (MART-1) melanoma Ag-reactive tumor-infiltrating lymphocyte (TIL) clones from the tumors of five patients. These MART-1-reactive clones displayed a wide variety of cellular avidities. α and β TCR genes were isolated from these clones, and TCR RNA was electroporated into the same non-MART-1-reactive allogeneic donor PBMC and TIL. TCR recipient cells gained the ability to recognize both MART-1 peptide and MART-1-expressing tumors in vitro, with avidities that closely corresponded to the original TCR clones (p = 0.018–0.0003). Clone DMF5, from a TIL infusion that mediated tumor regression clinically, showed the highest avidity against MART-1 expressing tumors in vitro, both endogenously in the TIL clone, and after RNA electroporation into donor T cells. Thus, we demonstrated that the TCR appeared to be the core determinant of MART-1 Ag-specific cellular avidity in these activated T cells and that nonreactive PBMC or TIL could be made tumor-reactive with a specific and predetermined avidity. We propose that inducing expression of this highly avid TCR in patient PBMC has the potential to induce tumor regression, as an “off-the-shelf” reagent for allogeneic melanoma patient gene therapy.
Spleen Tyrosine Kinase (Syk), a Novel Target of Curcumin, Is Required for B Lymphoma Growth
Authors: Gururajan Murali , Dasu Trivikram , Shahidain Seif , Jennings C. Darrell , Robertson Darrell A. , Rangnekar Vivek M. , Bondada Subbarao 
Published: April 2014

AbstractCurcumin (diferuloylmethane), a component of dietary spice turmeric (Curcuma longa), has been shown in recent studies to have therapeutic potential in the treatment of cancer, diabetes, arthritis, and osteoporosis. We investigated the ability of curcumin to modulate the growth of B lymphomas. Curcumin inhibited the growth of both murine and human B lymphoma in vitro and murine B lymphoma in vivo. We also demonstrate that curcumin-mediated growth inhibition of B lymphoma is through inhibition of the survival kinase Akt and its key target Bad. However, in vitro kinase assays show that Akt is not a direct target of curcumin. We identified a novel target for curcumin in B lymphoma viz spleen tyrosine kinase (Syk). Syk is constitutively activated in primary tumors and B lymphoma cell lines and curcumin down-modulates Syk activity accompanied by down-regulation of Akt activation. Moreover, we show that overexpression of Akt, a target of Syk, or Bcl-xL, a target of Akt can overcome curcumin-induced apoptosis of B lymphoma cells. These observations suggest a novel growth promoting role for Syk in lymphoma cells.
Feedback Regulation of Murine Autoimmunity via Dominant Anti-Inflammatory Effects of Interferon γ
Authors: Minguela Alfredo , Pastor Silvia , Mi Wentao , Richardson James A. , Ward E. Sally 
Published: April 2014

AbstractThere is a paucity of knowledge concerning the immunologic sequelae that culminate in overt autoimmunity. In the present study, we have analyzed the factors that lead to disease in the model of autoimmunity, murine experimental autoimmune encephalomyelitis (EAE). EAE in H-2u mice involves autoreactive CD4+ T cells that are induced by immunization with the immunodominant N-terminal epitope of myelin basic protein. The affinity of this epitope for I-Au can be increased by substituting lysine at position 4 with tyrosine, and this can be used to increase the effective Ag dose. Paradoxically, high doses of Ag are poorly encephalitogenic. We have used quantitative analyses to study autoreactive CD4+ T cell responses following immunization of mice with Ag doses that are at the extremes of encephalitogenicity. A dose of autoantigen that is poorly encephalitogenic results in T cell hyperresponsiveness, triggering an anti-inflammatory feedback loop in which IFN-γ plays a pivotal role. Our studies define a regulatory mechanism that serves to limit overly robust T cell responses. This feedback regulation has broad relevance to understanding the factors that determine T cell responsiveness.
Dectin-1 Interaction with Tetraspanin CD37 Inhibits IL-6 Production
Authors: Meyer-Wentrup Friederike , Figdor Carl G. , Ansems Marleen , Brossart Peter , Wright Mark D. , Adema Gosse J. , van Spriel Annemiek B. 
Published: April 2014

Abstract
C-type lectins are pattern-recognition receptors important for pathogen binding and uptake by APCs. Evidence is accumulating that integration of incoming cellular signals in APCs is regulated by grouping of receptors and signaling molecules into organized membrane complexes, such as lipid rafts and tetraspanin microdomains. In this study, we demonstrate that C-type lectin dectin-1 functionally interacts with leukocyte-specific tetraspanin CD37. Dectin-1 and CD37 colocalize on the surface of human APCs. Importantly, macrophages of CD37-deficient (CD37−/−) mice express decreased dectin-1 membrane levels, due to increased dectin-1 internalization. Furthermore, transfection of CD37 into a macrophage cell line elevated endogenous dectin-1 surface expression. Although CD37 deficiency does not affect dectin-1-mediated phagocytosis, we observed a striking 10-fold increase of dectin-1-induced IL-6 production in CD37−/− macrophages compared with wild-type cells, despite reduced dectin-1 cell surface expression. Importantly, the observed increase in IL-6 production was specific for dectin-1, because signaling via other pattern-recognition receptors was unaffected in CD37−/− macrophages and because the dectin-1 ligand curdlan was used. Taken together, these findings show that tetraspanin CD37 is important for dectin-1 stabilization in APC membranes and controls dectin-1-mediated IL-6 production.
Th3 Cells in Peripheral Tolerance. I. Induction of Foxp3-Positive Regulatory T Cells by Th3 Cells Derived from TGF-β T Cell-Transgenic Mice
Authors: Carrier Yijun , Yuan Jing , Kuchroo Vijay K. , Weiner Howard L. 
Published: April 2014

Abstract
TGF-β has been shown to be critical in the generation of CD4+CD25+Foxp3+ regulatory T cells (Tregs). Because Th3 cells produce large amounts of TGF-β, we asked whether induction of Th3 cells in the periphery was a mechanism by which CD4+CD25+ Tregs were induced in the peripheral immune compartment. To address this issue, we generated a TGF-β1-transgenic (Tg) mouse in which TGF-β is linked to the IL-2 promoter and T cells transiently overexpress TGF-β upon TCR stimulation but produce little or no IL-2, IL-4, IL-10, IL-13, or IFN-γ. Naive TGF-β-Tg mice are phenotypically normal with comparable numbers of lymphocytes and thymic-derived Tregs. We found that repeated antigenic stimulation of pathogenic myelin oligodendrocyte glycoprotein (MOG)-specific CD4+CD25− T cells from TGF-β Tg mice crossed to MOG TCR-Tg mice induced Foxp3 expression in both CD25+ and CD25− populations. Both CD25 subsets were anergic and had potent suppressive properties in vitro and in vivo. Furthermore, adoptive transfer of these induced regulatory CD25+/− T cells suppressed experimental autoimmune encephalomyelitis when administrated before disease induction or during ongoing experimental autoimmune encephalomyelitis. The suppressive effect of TGF-β on T cell responses was due to the induction of Tregs and not to the direct inhibition of cell proliferation. The differentiation of Th3 cells in vitro was TGF-β dependent as anti-TGF-β abrogated their development. Thus, Ag-specific TGF-β-producing Th3 cells play a crucial role in inducing and maintaining peripheral tolerance by driving the differentiation of Ag-specific Foxp3+ regulatory cells in the periphery.
IFN-γ Negatively Regulates CpG-Induced IL-10 in Bone Marrow-Derived Dendritic Cells
Authors: Flores Rafael R. , Diggs Kelly A. , Tait Lauren M. , Morel Penelope A. 
Published: April 2014

Abstract
Dendritic cells (DCs) are important players in the regulation of Th1- and Th2-dominated immune responses. In these studies we showed that IFN-γ, the key mediator of Th1 immunity, actively suppressed the production of IL-10 in murine DCs when activated with LPS or CpG. Our analysis revealed that both LPS and CpG induced IL-10 and IL-12 production but that the presence of IFN-γ, in a dose-dependent manner, suppressed the production of IL-10 while enhancing that of IL-12. The observed inhibition of IL-10 production was independent of IL-12. Experiments performed with STAT-1 knockout mice demonstrated that the primary production of IL-12 induced by CpG was STAT-1 dependent, whereas the production of IL-10 was not. This finding was confirmed by the observation that CpG-induced IL-12 production could be inhibited by anti-IFN-β Abs, whereas CpG-induced IL-10 production could not be inhibited. These data also demonstrated that the inhibitory effect of IFN-γ on IL-10 expression was STAT-1 dependent and transcriptionally regulated. Thus, DCs respond to CpG by producing proinflammatory and anti-inflammatory cytokines such as IL-12 and IL-10, respectively, and IFN-γ acts to not only enhance IL-12 but also to inhibit IL-10 production. The current data demonstrate a novel pathway for IFN-γ-mediated immunoregulation and suggest that IFN-γ-dependent suppression of IL-10 production by DCs may be involved in the antagonism between Th1 and Th2 patterns of immune reactivity.
FoxP3+ T Cells Undergo Conventional First Switch to Lymphoid Tissue Homing Receptors in Thymus but Accelerated Second Switch to Nonlymphoid Tissue Homing Receptors in Secondary Lymphoid Tissues
Authors: Lee Jee H. , Kang Seung G. , Kim Chang H. 
Published: April 2014

Abstract
Forkhead box P3 (FoxP3)-positive T cells are a specialized T cell subset for immune regulation and tolerance. We investigated the trafficking receptor switches of FoxP3+ T cells in thymus and secondary lymphoid tissues and the functional consequences of these switches in migration. We found that FoxP3+ T cells undergo two discrete developmental switches in trafficking receptors to migrate from primary to secondary and then to nonlymphoid tissues in a manner similar to conventional CD4+ T cells as well as unique to the FoxP3+ cell lineage. In the thymus, precursors of FoxP3+ cells undergo the first trafficking receptor switch (CCR8/CCR9→CXCR4→CCR7), generating mostly homogeneous CD62L+CCR7+CXCR4lowFoxP3+ T cells. CXCR4 expression is regained in FoxP3+ thymic emigrants in the periphery. Consistent with this switch, recent FoxP3+ thymic emigrants migrate exclusively to secondary lymphoid tissues but poorly to nonlymphoid tissues. The FoxP3+ thymic emigrants undergo the second switch in trafficking receptors for migration to nonlymphoid tissues upon Ag priming. This second switch involves down-regulation of CCR7 and CXCR4 but up-regulation of a number of memory/effector type homing receptors, resulting in generation of heterogeneous FoxP3+ T cell subsets expressing various combinations of trafficking receptors including CCR2, CCR4, CCR6, CCR8, and CCR9. A notable difference between the FoxP3+ and FoxP3− T cell populations is that FoxP3+ T cells undergo the second homing receptor switch at a highly accelerated rate compared with FoxP3− T cells, generating FoxP3+ T cells with unconventionally efficient migratory capacity to major nonlymphoid tissues.
Cutting Edge: Allele-Specific and Peptide-Dependent Interactions between KIR3DL1 and HLA-A and HLA-B
Authors: Thananchai Hathairat , Gillespie Geraldine , Martin Maureen P. , Bashirova Arman , Yawata Nobuyo , Yawata Makoto , Easterbrook Philippa , McVicar Daniel W. , Maenaka Katsumi , Parham Peter , Carrington Mary , Dong Tao , Rowland-Jones Sarah 
Published: April 2014

Abstract
Although it is clear that KIR3DL1 recognizes Bw4+ HLA-B, the role of Bw4+ HLA-A allotypes as KIR3DL1 ligands is controversial. We therefore examined the binding of tetrameric HLA-A and –B complexes, including HLA*2402, a common Bw4+ HLA-A allotype, to KIR3DL1*001, *005, *007, and *1502 allotypes. Only Bw4+ tetramers bound KIR3DL1. Three of four HLA-A*2402 tetramers bound one or more KIR3DL1 allotypes and all four KIR3DL1 allotypes bound to one or more HLA-A*2402 tetramers, but with different binding specificities. Only KIR3DL1*005 bound both HLA-A*2402 and HLA-B*5703 tetramers. HLA-A*2402-expressing target cells were resistant to lysis by NK cells expressing KIR3DL1*001 or *005. This study shows that HLA-A*2402 is a ligand for KIR3DL1 and demonstrates how the binding of KIR3DL1 to Bw4+ ligands depends upon the bound peptide as well as HLA and KIR3DL1 polymorphism.
Loss of Src Homology Region 2 Domain-Containing Protein Tyrosine Phosphatase-1 Increases CD8+ T Cell-APC Conjugate Formation and Is Associated with Enhanced In Vivo CTL Function
Authors: Sathish Jean G. , Dolton Garry , LeRoy Frances G. , Matthews R. James 
Published: April 2014

Abstract
Extensive evidence has been accumulated to implicate the intracellular protein tyrosine phosphatase, Src homology region 2 domain-containing protein tyrosine phosphatase-1 (SHP-1), as a negative regulator of TCR-signaling thresholds. Specifically, T cells from the SHP-1-deficient mouse, motheaten, exhibit a hyperproliferative phenotype when activated by cognate peptide-pulsed APCs. However, the cellular basis for this phenotype has not been fully explained. Using the intracellular fluorescent dye, CFSE, we show that a greater proportion of motheaten vs control naive CD8+ T cells undergo cell division when activated by peptide-pulsed APCs. Furthermore, there is a greater likelihood of TCRs on SHP-1-deficient vs control T cells binding to peptide/MHC ligands on APCs when using TCR down-regulation as an indirect measure of TCR engagement. In addition, T cell-APC conjugate assays provide direct evidence that a greater proportion of SHP-1-deficient T cells are capable of forming stable conjugates with APCs and this may explain, at least in part, their hyperproliferative response to TCR-triggered stimulation. The physiological relevance of the combined in vitro observations is demonstrated by the significantly enhanced in vivo expansion and CTL capacity generated in mice receiving adoptively transferred SHP-1-deficient naive CD8+ T cells when compared with control T cells.
Brahma-Related Gene 1-Dependent STAT3 Recruitment at IL-6-Inducible Genes
Authors: Ni Zuyao , Bremner Rod 
Published: April 2014

Abstract
IL-6 is an immunoregulatory cytokine with multiple functions in hemopoiesis, proliferation, and tumorigenesis. IL-6 triggers phosphorylation, dimerization, and nuclear translocation of STAT3, which binds to target promoters and activates transcription. Brahma-related gene 1 (BRG1), the enzymatic engine of the yeast-mating type-switching and sucrose-nonfermenting chromatin-remodeling complex, is essential for recruitment of STAT1 or STAT1/STAT2-containing complexes to IFN targets. We hypothesized that BRG1 might also be required for STAT3 recruitment. In this study, we show that induction of a subset of human IL-6-responsive genes is BRG1 dependent. BRG1 is constitutively present at these targets and is required for STAT3 recruitment, downstream histone modifications, and IL-6-induced chromatin remodeling. IL-6-induced recruitment of STAT3 to the IFN regulatory factor 1 promoter and subsequent mRNA synthesis is BRG1 dependent, even though IFN-γ-mediated STAT1 recruitment to this locus is BRG1 independent. BRG1 also increased basal expression of IFN-induced transmembrane protein 3 and IFN-γ-induced protein 16, and the basal chromatin accessibility at the promoter of IFN regulatory factor 1. The effect on basal expression was STAT3 independent, as revealed by small interfering RNA knockdown. Together with prior observations, these data reveal that BRG1 has a broad role in mediating STAT accessibility at multiple cytokine-responsive promoters and exposes promoter specific differences in both the effect of BRG1 on basal chromatin accessibility and on access of different STAT proteins to the same target.
Decay-Accelerating Factor Must Bind Both Components of the Complement Alternative Pathway C3 Convertase to Mediate Efficient Decay
Authors: Harris Claire L. , Pettigrew David M. , Lea Susan M. , Morgan B. Paul 
Published: April 2014

AbstractDecay-accelerating factor (DAF; CD55) inhibits the complement (C) cascade by dissociating the multimolecular C3 convertase enzymes central to amplification. We have previously demonstrated using surface plasmon resonance (Biacore International) that DAF mediates decay of the alternative pathway C3 convertase, C3bBb, but not of the inactive proenzyme, C3bB, and have shown that the major site of interaction is with the larger cleavage subunit factor B (Bb) subunit. In this study, we dissect these interactions and demonstrate that the second short consensus repeat (SCR) domain of DAF (SCR2) interacts only with Bb, whereas SCR4 interacts with C3b. Despite earlier studies that found SCR3 to be critical to DAF activity, we find that SCR3 does not directly interact with either subunit. Furthermore, we demonstrate that properdin, a positive regulator of the alternative pathway, does not directly interact with DAF. Extending from studies of binding to decay-accelerating activity, we show that truncated forms of DAF consisting of SCRs 2 and 3 bind the convertase stably via SCR2-Bb interactions but have little functional activity. In contrast, an SCR34 construct mediates decay acceleration, presumably due to SCR4-C3b interactions demonstrated above, because SCR3 alone has no binding or functional effect. We propose that DAF interacts with C3bBb through major sites in SCR2 and SCR4. Binding to Bb via SCR2 increases avidity of binding, concentrating DAF on the active convertase, whereas more transient interactions through SCR4 with C3b directly mediate decay acceleration. These data provide new insights into the mechanisms involved in C3 convertase decay by DAF.
Critical Residues at the Ly49 Natural Killer Receptor’s Homodimer Interface Determine Functional Recognition of m157, a Mouse Cytomegalovirus MHC Class I-Like Protein
Authors: Kielczewska Agnieszka , Kim Hee-Seo , Lanier Lewis L. , Dimasi Nazzareno , Vidal Silvia M. 
Published: April 2014

AbstractNK cell function is regulated by Ly49 receptors in mice and killer cell Ig-like receptors in humans. Although inhibitory Ly49 and killer cell Ig-like receptors predominantly ligate classical MHC class I molecules, recent studies suggest that their activating counterparts recognize infection. The quintessential example is resistance to the mouse CMV in C57BL/6 mice, which depends on the functional recognition of m157, a mouse CMV-encoded MHC class I-like molecule, by Ly49H, an activating NK cell receptor. We have taken advantage of the natural variation in closely related members of the Ly49C-like receptors and the availability of Ly49 crystal structures to understand the molecular determinants of the Ly49H-m157 interaction and to identify amino acid residues discriminating between m157 binding and nonbinding receptors. Using a site-directed mutagenesis approach, we have targeted residues conserved in receptors binding to m157 (Ly49H and Ly49I129) but different from receptors lacking m157 recognition (Ly49C, Ly49IB6, and Ly49U). Wild-type and mutant receptors were transfected into reporter cells, and physical binding as well as functional activation by m157 was studied. Our findings suggested that the Ly49 MHC class I contact “site 2,” I226, may not be involved in m157 binding. In contrast, residue Y146 and G151, mapping at the receptor homodimer interface, are likely critical for functional recognition of the m157 glycoprotein. Our combined functional and three-dimensional modeling approach suggested that the architecture of the Ly49H dimer is crucial to accessing m157, but not MHC class I. These results link Ly49 homodimerization variability to the direct recognition of pathogen products.