bluuebunny/crossref_metadata_2025_split huggingface dataset:
γ-Aminobutyric Acid Inhibits T Cell Autoimmunity and the Development of Inflammatory Responses in a Mouse Type 1 Diabetes Model
Authors: Tian Jide , Lu Yuxin , Zhang Hanwei , Chau Cindy H. , Dang Hoa N. , Kaufman Daniel L. 
Published: April 2014

Abstract
γ-Aminobutyric acid (GABA) is both a major inhibitory neurotransmitter in the CNS and a product of β cells of the peripheral islets. Our previous studies, and those of others, have shown that T cells express functional GABAA receptors. However, their subunit composition and physiological relevance are unknown. In this study, we show that a subset of GABAA receptor subunits are expressed by CD4+ T cells, including the δ subunit that confers high affinity for GABA and sensitivity to alcohol. GABA at relatively low concentrations down-regulated effector T cell responses to β cell Ags ex vivo, and administration of GABA retarded the adoptive transfer of type 1 diabetes (T1D) in NOD/scid mice. Furthermore, treatment with low dose of GABA (600 μg daily) dramatically inhibited the development of proinflammatory T cell responses and disease progression in T1D-prone NOD mice that already had established autoimmunity. Finally, GABA inhibited TCR-mediated T cell cycle progression in vitro, which may underlie GABA’s therapeutic effects. The immunoinhibitory effects of GABA on T cells may contribute to the long prodomal period preceding the development of T1D, the immunological privilege of the CNS, and the regulatory effects of alcohol on immune responses. Potentially, pharmacological modulation of GABAA receptors on T cells may provide a new class of therapies for human T1D as well as other inflammatory diseases.
Mechanisms of Soluble Cytokine Receptor Generation
Authors: Levine Stewart J. 
Published: April 2014

Abstract
Soluble cytokine receptors regulate inflammatory and immune events by functioning as agonists or antagonists of cytokine signaling. As such, they act within complex receptor systems that include signaling receptors, nonsignaling decoy receptors, receptor-associated proteins, and soluble receptor antagonists. Soluble cytokine receptors can be generated by several mechanisms, which include proteolytic cleavage of receptor ectodomains, alternative splicing of mRNA transcripts, transcription of distinct genes that encode soluble cytokine-binding proteins, release of full-length receptors within the context of exosome-like vesicles, and cleavage of GPI-anchored receptors. Furthermore, the important role of soluble cytokine receptors in regulating host defense mechanisms is evidenced by viruses that encode soluble homologues of mammalian receptors and thereby evade innate host immune responses via the sequestration of essential cytokines.
Deranged Early T Cell Development in Immunodeficient Strains of Nonobese Diabetic Mice
Authors: Yui Mary A. , Rothenberg Ellen V. 
Published: April 2014

Abstract
NOD mice exhibit defects in T cell functions that have been postulated to contribute to diabetes susceptibility in this strain. However, early T cell development in NOD mice has been largely unexplored. NOD mice with the scid mutation and Rag1 deficiency were analyzed for pre-T cell development in the NOD genetic background. These strains reveal an age-dependent, programmed breakdown in β selection checkpoint enforcement. At 5–8 wk of age, even in the absence of TCRβ expression, CD4+ and CD4+CD8+ blasts appear spontaneously. However, these breakthrough cells fail to restore normal thymic cellularity. The breakthrough phenotype is recessive in hybrid (NOD×B6)F1-scid and -Rag1null mice. The breakthrough cells show a mosaic phenotype with respect to components of the β selection program. They mimic normal β selection by up-regulating germline TCR-Cα transcripts, CD2, and Bcl-xL and down-regulating Bcl-2. However, they fail to down-regulate transcription factors HEB-alt and Hes1 and initially express aberrantly high levels of Spi-B, c-kit (CD117), and IL-7Rα. Other genes examined distinguish this form of breakthrough from previously reported models. Some of the abnormalities appear first in a cohort of postnatal thymocytes as early as the double-negative 2/double-negative 3 transitional stage. Thus, our results reveal an NOD genetic defect in T cell developmental programming and checkpoint control that permits a subset of the normal outcomes of pre-TCR signaling to proceed even in the absence of TCRβ rearrangement. Furthermore, this breakthrough may initiate thymic lymphomagenesis that occurs with high frequency in both NOD-scid and -Rag1null mice.
Rapid Induction of Splenic and Peritoneal B-1a Cells in Adult Mice by Thymus-Independent Type-2 Antigen
Authors: Whitmore Alan C. , Neely Harold R. , Diz Ramiro , Flood Patrick M. 
Published: April 2014

AbstractWe have produced a transgenic mouse (PV1TgL) that can only generate B lymphocytes with an Ig receptor specific for the synthetic polymer polyvinyl pyrrolidinone. Before immunization, bone marrow B cell numbers are very low, and peripheral lymphoid organs are almost devoid of B cells, confirming the role of positive selection by Ag in the development of mature B cell populations. The predominant population of B cells in the spleens of naive adult PV1TgL mice have most of the characteristics of marginal zone B cells, including anatomical location in the peripheral areas of the splenic white pulp. After immunization, a new population of B cells appears in the spleen with the characteristics of B-1 cells. Similar cells also appear somewhat later in the peritoneal cavity. Our findings suggest that immunization with a thymus-independent Ag can lead to the appearance and expansion of Ag-reactive B-1 cells in an adult mouse.
The Selective Increase in Caspase-3 Expression in Effector but Not Memory T Cells Allows Susceptibility to Apoptosis
Authors: Sabbagh Laurent , Kaech Susan M. , Bourbonnière Martin , Woo Minna , Cohen Luchino Y. , Haddad Elias K. , Labrecque Nathalie , Ahmed Rafi , Sékaly Rafick-Pierre 
Published: April 2014

AbstractCaspases play a central role in T lymphocyte activation and death. We have demonstrated previously that caspase-3, an effector molecule for activation-induced cell death (AICD), is processed following T cell activation in the absence of apoptosis. We report in this study that caspase-3 mRNA levels were selectively increased in peripheral T cells, following Ag receptor-mediated activation. The up-regulation of caspase-3 mRNA was confined to cells in the early phases of the cell cycle (G0/G1) and was independent of IL-2 signaling. This increase led to the renewal of procaspase-3 as evidenced by a 6-fold up-regulation of the zymogen in nonapoptotic stimulated T cells. The increase of mRNA levels and of both the zymogen and the cleaved forms of caspase-3 was observed in in vivo stimulated Ag-specific effector, but not memory T cells, correlating with the enhanced susceptibility of effector T cells to AICD. Furthermore, we confirm that caspase-3 levels directly influence the sensitivity of activated T cells to apoptosis, as shown using T lymphocytes isolated from caspase-3 heterozygous and knockout mice. These findings indicate that the selective up-regulation of caspase-3 transcription is required to maintain the cytoplasmic levels of this protease, which control AICD and T cell homeostasis.
Functionally Impaired HIV-Specific CD8 T Cells Show High Affinity TCR-Ligand Interactions
Authors: Ueno Takamasa , Tomiyama Hiroko , Fujiwara Mamoru , Oka Shinichi , Takiguchi Masafumi 
Published: April 2014

AbstractWe eventually isolated two different clonotypic CD8 T cell subsets recognizing an HIV Pol-derived epitope peptide (IPLTEEAEL) in association with HLA-B35 from a chronic HIV-infected patient. By kinetic analysis experiments, the subsets showed a &gt;3-fold difference in half-lives for the HLA tetramer in complex with the Pol peptide. In functional assays in vitro and ex vivo, both subsets showed substantial functional avidity toward peptide-loaded cells. However, the high affinity subset did not show cytolytic activity, cytokine production, or proliferation activity toward HIV-infected cells, whereas the moderate affinity one showed potent activities. Furthermore, using ectopic expression of each of the TCR genes into primary human CD8 T cells, the CD8 T cells transduced with the high affinity TCR showed greater binding activity toward the tetramer and impaired cytotoxic activity toward HIV-infected cells, corroborating the results obtained with parental CD8 T cells. Taken together, these data indicate that impaired responsiveness of T cells toward HIV-infected cells can occur at the level of TCR-ligand interactions, providing us further insight into the immune evasion mechanisms by HIV.
Prostaglandin E2-Dependent Enhancement of Tissue Inhibitors of Metalloproteinases-1 Production Limits Dendritic Cell Migration through Extracellular Matrix
Authors: Baratelli Felicita E. , Heuzé-Vourc’h Nathalie , Krysan Kostyantyn , Dohadwala Mariam , Riedl Karen , Sharma Sherven , Dubinett Steven M. 
Published: April 2014

AbstractDendritic cell (DC) migration is crucial for the initiation of immune responses. The balance between metalloproteinases (MMP) and tissue inhibitors of metalloproteinases (TIMP) has been shown to modulate DC migration. PGE2, which is overproduced in a wide variety of human malignancies, has been implicated in MMP and TIMP regulation in various cells, including monocytes. In the present study, we hypothesized that tumor-derived PGE2 would affect DC migratory capacity through the extracellular matrix (ECM) by altering MMP and TIMP balance. Treatment of monocyte-derived immature DC with exogenous PGE2 induced TIMP-1 secretion but not MMP-9 production and was correlated with reduced DC migration through ECM. Because recombinant TIMP-1 replicated PGE2 inhibition of DC migration while anti-TIMP-1 neutralizing Ab reversed it, we conclude that PGE2-mediated induction of TIMP-1 was responsible for the reduced migration of PGE2-treated DC. Similarly, DC cultured for 48 h in supernatants from cyclooxygenase-2 overexpressing lung cancer cells that secrete high levels of PGE2, exhibited decreased migration through ECM. Finally, analysis of E prostanoid receptor expression and their selective inhibition revealed that the enhanced TIMP-1 secretion in PGE2-treated DC was mediated predominantly by the E prostanoid receptor 2. These findings indicate that PGE2-dependent enhancement of TIMP-1 production causes reduced migration of DC through ECM.
Target Antigens Determine Graft-versus-Host Disease Phenotype
Authors: Kaplan Daniel H. , Anderson Britt E. , McNiff Jennifer M. , Jain Dhanpat , Shlomchik Mark J. , Shlomchik Warren D. 
Published: April 2014

AbstractChronic graft-vs-host disease (cGVHD) is an increasingly frequent complication of allogeneic stem cell transplantation. Phenotypically, cGVHD differs from patient to patient; in particular, a subset of patients develops extensive cutaneous fibrosis. Similarly, graft-vs-host disease (GVHD) is distinct in inbred murine donor:recipient pairings, indicating a genetic component to disease phenotype. The B10.D2 → BALB/c (H-2d) strain pairing uniquely recapitulates key pathologic features of fibrotic human cutaneous cGVHD. To distinguish whether this genetic component is due to differences in genes that modulate immune responses or to the specific Ags targeted, we asked whether skin-dominant cGVHD also develops in the B10 → BALB.B (H-2b) and B10.BR → BALB.K (H-2k) MHC-congenic pairings. Because each MHC haplotype presents different peptides and selects different T cell repertoires, GVHD in each donor:recipient pair undoubtedly targets different Ags. We found that, in contrast to BALB/c recipients, BALB.B mice never manifested skin disease while BALB.K mice developed a modified form of skin disease. Instead, BALB.B and BALB.K recipients developed systemic GVHD which was absent in BALB/c mice. Moreover, in (B10 × B10.D2)F1 → (BALB.B × BALB/c)F1 H-2b/d transplants, recipients developed both cutaneous and systemic disease. Thus, the selection of immunodominant Ags determines the target and character of GVHD, providing insight into the genetic basis for different forms of GVHD.
Evolution of Transcriptional Control of theIgHLocus: Characterization, Expression, and Function of TF12/HEB Homologs of the Catfish
Authors: Hikima Jun-ichi , Cioffi Christopher C. , Middleton Darlene L. , Wilson Melanie R. , Miller Norman W. , Clem L. William , Warr Gregory W. 
Published: April 2014

AbstractThe transcriptional enhancer (Eμ3′) of the IgH locus of the channel catfish, Ictalurus punctatus, differs from enhancers of the mammalian IgH locus in terms of its position, structure, and function. Transcription factors binding to multiple octamer motifs and a single μE5 motif (an E-box site, consensus CANNTG) interact for its function. E-box binding transcription factors of the class I basic helix-loop-helix family were cloned from a catfish B cell cDNA library in this study, and homologs of TF12/HEB were identified as the most highly represented E-proteins. Two alternatively spliced forms of catfish TF12 (termed CFEB1 and -2) were identified and contained regions homologous to the basic helix-loop-helix and activation domains of other vertebrate E-proteins. CFEB message is widely expressed, with CFEB1 message predominating over that of CFEB2. Both CFEB1 and -2 strongly activated transcription from a μE5-dependent artificial promoter. In catfish B cells, CFEB1 and -2 also activated transcription from the core region of the catfish IgH enhancer (Eμ3′) in a manner dependent on the presence of the μE5 site. Both CFEB1 and -2 bound the μE5 motif, and formed both homo- and heterodimers. CFEB1 and -2 were weakly active or inactive (in a promoter-dependent fashion) in mammalian B-lineage cells. Although E-proteins have been highly conserved in vertebrate evolution, the present results indicate that, at the phylogenetic level of a teleost fish, the TF12/HEB homolog differs from that of mammals in terms of 1) its high level of expression and 2) the presence of isoforms generated by alternative RNA processing.
CD4 Phosphorylation Partially Reverses Nef Down-Regulation of CD4
Authors: Jin Yong-Jiu , Zhang Xiaoping , Boursiquot J. Gildade , Burakoff Steven J. 
Published: April 2014

Abstract
HIV Nef down-regulates CD4 from the cell surface in the absence of CD4 phosphorylation, whereas PMA down-regulates CD4 through a phosphorylation-dependent pathway. In this study we show that the down-regulation of CD4 in human Jurkat T cells expressing Nef was nearly complete (∼95%), whereas that induced by PMA was partial (∼40%). Unexpectedly, treating T cells expressing Nef with PMA restored the surface CD4 up to 35% of the steady state level. Both mutating the phosphorylation sites in the CD4 cytoplasmic tail (Ser408 and Ser415) and the use of a protein kinase C inhibitor, bisindolylmaleimide1, abolished the restoration of surface CD4, suggesting that the restoration required CD4 phosphorylation. CD4 and Nef could be cross-linked by a chemical cross-linker, 3,3-dithiobis[sulfosuccinimidyl-propionate], in control T cell membranes, but not in PMA-treated T cell membrane, suggesting that CD4 and Nef interacted with each other in T cells, and the phosphorylation disrupted the CD4-Nef interaction. We propose that this dissociation switches CD4 internalization from the Nef-mediated, nearly complete down-regulation to a phosphorylation-dependent, partial down-regulation, resulting in a net gain of CD4 on the T cell surface.
Altered Th1 Cell Differentiation Programming by CIITA Deficiency
Authors: Patel Dipak R. , Kaplan Mark H. , Chang Cheong-Hee 
Published: April 2014

Abstract
CD4 T cell differentiation is a complex process affected by many transcription factors interacting in a tightly regulated manner. We have previously shown that CIITA-deficient mouse Th1 cells expressed Th2-type cytokines, while IFN-γ expression was normal. In this study, we show that CIITA-deficient Th1 cells contain three distinct populations: cells secreting IL-4 alone, IFN-γ alone, and both IL-4 and IFN-γ together. This novel phenotype is stable over multiple rounds of stimulation in the presence of Th1-inducing factors. CIITA-deficient Th1 cells require TCR-mediated signaling to express Th2 cytokines, and this occurs with similar kinetics as wild-type Th2 cells. Both GATA-3 and IL-4 appear to be required for CIITA-deficient Th1 cells to express Th2-type cytokines. Interestingly, however, CIITA-deficient Th1 cells can produce IL-4 in the absence of exogenous IL-4. Introducing either CIITA or antisense GATA-3 during Th1 differentiation partially reduces Th2-type cytokine expression. With the exception of Th2-type cytokine expression, Th1 differentiation occurs normally in the absence of CIITA, as measured by expression of T-bet, IL-12Rβ2, IL-18Rα, and IFN-γ. Therefore, CIITA plays a key role to repress Th2-type cytokine expression as naive CD4 T cells differentiate toward the Th1 lineage.
B Lymphocyte-Induced Maturation Protein (Blimp)-1, IFN Regulatory Factor (IRF)-1, and IRF-2 Can Bind to the Same Regulatory Sites
Authors: Kuo Tracy C. , Calame Kathryn L. 
Published: April 2014

Abstract
The transcriptional repressor B lymphocyte-induced maturation protein-1 (Blimp-1) is expressed in some differentiated cells and is required for terminal differentiation of B cells. To facilitate identification of Blimp-1 target genes, we have determined the optimal DNA recognition sequence for Blimp-1. The consensus is very similar to a subset of sites recognized by IFN regulatory factors (IRFs) that contain the sequence GAAAG. By binding competition and determination of equilibrium dissociation constants, we show that Blimp-1, IRF-1, and IRF-2 have similar binding affinities for functionally important regulatory sites containing this sequence. However, Blimp-1 does not bind to all IRF sites, and specifically does not recognize IRF-4/PU.1 or IRF-8 sites lacking the GAAAG sequence. Chromatin immunoprecipitation studies showed that Blimp-1, IRF-1, and IRF-2 all bind the IFN-β promoter in vivo, as predicted by the in vitro binding parameters, and in cotransfections Blimp-1 inhibits IRF-1-dependent activation of the IFN-β promoter. Thus, our data suggest that Blimp-1 competes in vivo with a subset of IRF proteins and help predict the sites and IRF family members that may be affected.
The Interaction between GATA Proteins and Activator Protein-1 Promotes the Transcription ofIL-13in Mast Cells
Authors: Masuda Akio , Yoshikai Yasunobu , Kume Hiroaki , Matsuguchi Tetsuya 
Published: April 2014

AbstractIL-13 is considered to be a key modulator in the pathogenesis of Th2-induced allergic inflammation, although little is known about the regulation of IL-13 transcription in mast cells. In T cells, involvement of GATA-3 in cell type-specific expression of the IL-13 gene has been reported. However, the mechanisms that induce rapid transactivation of the IL-13 gene in response to various types of stimulation have hitherto remained unknown. In this report, we describe our investigation of the promoter region necessary for IL-13 transcription; we have found that both AP-1 and GATA proteins are indispensable for IL-13 transcription in mouse mast cells. In our investigation, we focused on the functional interaction between GATA and AP-1 in the IL-13 promoter context. Transfection experiments have revealed that GATA-1 and GATA-2 proteins are able to associate with AP-1 proteins. We have also shown that overexpression of GATA-1 induced excess AP-1 binding to the IL-13 promoter as well as a significant increase in IL-13 production in mast cells. The results of the present study have shown that direct interaction between AP-1 and GATA proteins plays an important role in IL-13 transcription in mast cells.
Shark Ig Light Chain Junctions Are as Diverse as in Heavy Chains
Authors: Fleurant Marshall , Changchien Lily , Chen Chin-Tung , Flajnik Martin F. , Hsu Ellen 
Published: April 2014

AbstractWe have characterized a small family of four genes encoding one of the three nurse shark Ig L chain isotypes, called NS5. All NS5 cDNA sequences are encoded by three loci, of which two are organized as conventional clusters, each consisting of a V and J gene segment that can recombine and one C region exon; the third contains a germline-joined VJ in-frame and the fourth locus is a pseudogene. This is the second nurse shark L chain type where both germline-joined and split V-J organizations have been found. Since there are only two rearranging Ig loci, it was possible for the first time to examine junctional diversity in defined fish Ig genes, comparing productive vs nonproductive rearrangements. N region addition was found to be considerably more extensive in length and in frequency than any other vertebrate L chain so far reported and rivals that in H chain. We put forth the speculation that the unprecedented efficiency of N region addition (87–93% of NS5 sequences) may be a result not only of simultaneous H and L chain rearrangement in the shark but also of processing events that afford greater accessibility of the V or J gene coding ends to terminal deoxynucleotidyltransferase.
Exclusion and Inclusion of TCRα Proteins during T Cell Development in TCR-Transgenic and Normal Mice
Authors: Lacorazza H. Daniel , Nikolich-Žugich Janko 
Published: April 2014

AbstractAllelic exclusion of immune receptor genes (and molecules) is incompletely understood. With regard to TCRαβ lineage T cells, exclusion at the tcr-b, but not tcr-a, locus seems to be strictly controlled at the locus rearrangement level. Consequently, while nearly all developing TCRαβ thymocytes express a single TCRβ protein, many thymocytes rearrange and express two different TCRα chains and, thus, display two αβTCRs on the cell surface. Of interest, the number of such dual TCR-expressing cells is appreciably lower among the mature T cells. To understand the details of TCR chain regulation at various stages of T cell development, we analyzed TCR expression in mice transgenic for two rearranged αβTCR. We discovered that in such TCR double-transgenic (TCRdTg) mice peripheral T cells were functionally monospecific. Molecularly, this monospecificity was due to TCRα exclusion: one transgenic TCRα protein was selectively down-regulated from the thymocyte and T cell surface. In searching for the mechanism(s) governing this selective TCRα down-regulation, we present evidence for the role of protein tyrosine kinase signaling and coreceptor involvement. This mechanism may be operating in normal thymocytes.
Conformational Restraints and Flexibility of 14-Meric Peptides in Complex with HLA-B*3501
Authors: Probst-Kepper Michael , Hecht Hans-Jürgen , Herrmann Hanne , Janke Viktoria , Ocklenburg Frank , Klempnauer Jürgen , van den Eynde Benoit J. , Weiss Siegfried 
Published: April 2014

Abstract
Human HLA-B*3501 binds an antigenic peptide of 14-aa length derived from an alternative reading frame of M-CSF with high affinity. Due to its extraordinary length, the exact HLA binding mode was unpredictable. The crystal structure of HLA-B*3501 at 1.5 Å shows that the N and C termini of the peptide are embedded in the A and F pockets, respectively, similar to a peptide of normal length. The central part of the 14-meric peptide bulges flexibly out of the groove. Two variants of the alternative reading frame of M-CSF peptide substituted at P2 or P2 and P9 with Ala display weak or no T cell activation. Their structure differs mainly in flexibility and conformation from the agonistic peptide. Moreover, the variants induce subtle changes of MHC α-helical regions implicated as critical for TCR contact. The TCR specifically recognizing this peptide/MHC complex exhibits CDR3 length within the normal range, suggesting major conformational adaptations of this receptor upon peptide/MHC binding. Thus, the potential antigenic repertoire recognizable by CTLs is larger than currently thought.