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The inhibitory immunoregulatory receptor CTLA-4 is critical in maintaining self-tolerance, but the mechanisms of its actions have remained controversial. Here we examined the antigen specificity of tissue-infiltrating CD4+ T cells in Ctla4−/− mice. After adoptive transfer, T cells isolated from tissues of Ctla4−/− mice showed T cell antigen receptor (TCR)-dependent accumulation in the tissues from which they were derived, which suggested reactivity to tissue-specific antigens. We identified the pancreas-specific enzyme PDIA2 as an autoantigen in Ctla4−/− mice. CTLA-4 expressed either on PDIA2-specific effector cells or on regulatory T cells was sufficient to control tissue destruction mediated by PDIA2-specific T cells. Our results demonstrate that both cell-intrinsic and non–cell-autonomous actions of CTLA-4 operate to maintain T cell tolerance to a self antigen. [ABSTRACT FROM AUTHOR]

Abstract: In the immune system, TGF-β1 exerts two major functions, anti-inflammatory and immuno-suppressive effects. This work aims to investigate the molecular mechanisms involved in the regulation of the TGF-β1 gene expression in CD4+ T cells. The TGF-β1 gene expresses three transcripts of 2.5, 1.9, and 1.4kb. The 1.9kb mRNA which has the highest translation activity was the major transcript. The relationship between T cell receptor (TCR) stimulation and the expression of the gene was investigated. TCR stimulation with a low dose of antigen peptide enhanced the gene expression, whereas a higher dose suppressed the expression. TCR stimulation activates PKC/MAPK and Ca2+ signaling pathways. PMA increased the gene expression, whereas ionomycin decreased the gene expression, markedly. The results indicate that Ca2+ signaling down-regulates TGF-β1 gene expression. The molecular regulation of TGF-β1 gene expression is unique when comparing to other cytokine genes which are generally activated by Ca2+ signaling. [Copyright &y& Elsevier]

In this study, we investigated the relationship between the expression levels of self-antigen and the function of self-reactive T cells in the periphery. To this end, we used two rat insulin promoter-ovalbumin (RIP-OVA) transgenic mice (RIP-OVAhigh, RIP-OVAlow) in which was produced only in pancreatic p-islet cells. The OVA-producing transgenic mice were crossed to DO.11.10 (DO) mice expressing a T cell antigen receptor specific for OVA323-339. The responsiveness of peripheral CD4+ T cells in the double transgenic mice was examined. We demonstrated that hyporesponsive but highly IL-10-producing T cells were developed in DO × OVAhigh mice only, not in DO × OVAlow mice. These IL-10-producing T cells exhibited regulatory activity both in in vitro and in vivo experiments. Moreover, these IL-10- producing regulatory T (Tr) cells expressed high levels of inducible costimulator (ICOS) before in vitro stimulation. Blockade of ICOS-signaling inhibited the production of IL-10 and abrogated the inhibitory function of these Tr cells. Thus, these results suggested that the development of IL-10-producing Tr cells depends on the expression levels of self-antigen in vivo and that ICOS signal plays a critical role in immune regulation by IL-10- producing Tr cells in self-tolerance. [ABSTRACT FROM AUTHOR]

Reports a study that analyzed the cytolytic activity of intra-epithelial T cells (IEL) isolated from the small intestines in different genes in which the number of IEL expressing either T cell receptor (TCR)-alpha and beta were absent or markedly diminished. Materials and methods of the study; Cytolytic activity of ...-IEL in mice; Phenotypic and gene usage analyses of ...-IEL mice.

During T cell development in the thymus, a certain population of self-reactive thymocytes differentiates into regulatory T cells that suppress otherwise harmful self-reactive T cells. In transgenic mice expressing both TCR that specifically recognizes moth cytochrome c and the moth cytochrome c ligand, a large proportion of CD4+ T cells expresses CD25 and secretes TGF-beta1 upon Ag stimulation. Because TGF-beta1 expression by these T cells can be decreased by cyclosporin A, a NF-AT inhibitor, NF-AT-mediated TGF-beta1 expression in T cells was addressed by characterizing a NF-AT response element in the TGF-beta1 promoter. Analysis of the mouse TGF-beta1 promoter (-1799 to +793) in transfection experiments in T cell 68-41 hybridoma cells detected NF-AT binding sites at positions +268 and +288 in the proximal promoter region. Binding of NF-AT to this region was detected only in tolerant CD4+ T cells, but not in fully activated CD4+ T cells by chromatin immunoprecipitation assays. Activation of these NF-AT sites was sufficient to induce TGF-beta1 promoter activity; however, additional signaling due to full Ag stimulation blocked NF-AT-mediated TGF-beta1 expression. This suppression of the TGF-beta1 promoter is mediated by the -1079 to -406 region, in which deletion of a GATA-binding motif at position -821 abrogates NF-AT-mediated activation of the TGF-beta1 promoter. Therefore, TGF-beta1 expression in T cells is controlled by multiple regulatory factors that have distinct functions in response to partial or full TCR activation.