RECEPTORS, CO-RECEPTORS, AND COUNTER-RECEPTORS IN T CELL ACTIVATION

T 细胞激活中的受体、共受体和反受体

• 批准号: 3768752
• 负责人: E M SHEVACH
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3768752
• 关键词: B lymphocyte; T cell receptor; T lymphocyte; cytokine; gene expression; immunoregulation; interleukin 4; laboratory mouse; leukocyte activation /transformation; ligands; macrophage; prolactin; staphylococcal enterotoxin; surface antigens

The interaction of the T cell receptor (TCR) with its specific ligand, peptide-MHC, is only one component of the events required for the activation of antigen-specific T cells. The primary goals of our studies are to characterize cell surface antigens (co-receptors) and their soluble or cell associated ligands (counter-receptors) which play critical roles in cell-cell interaction and in the interaction of T cells with their environment. We have concentrated out efforts in a number of distinct areas: 1) We have shown that the cytokine, interleukin-10 (IL-10), inhibits T cell activation by acting on macro-phages and not other types of accessory cells. We have further elucidated the mechanism of action of IL-10 on the inhibition of macrophage costimulatory activity and shown that IL-10 selectively inhibits the upregulation of expression of the B7 antigen which is the cellular counter-receptor for the T cell antigen CD28. The regulation of B7 expression by IL-10 may determine whether T cells become primed or are rendered non-responsive during the generation of an immune response. 2) One model of immunologic tolerance involves the induction peripheral T cell anergy by the injection of adult mice with Staphylococcal enterotoxins. To further characterize the state of a tolerant T cell in vivo, we have established an in vivo model that generates enterotoxin specific IL-4 production. This IL-4 pathway was highly susceptible to tolerogenic signals in both naive T cells and in T cells primed for IL-4 production. The tolerized IL-4 pathway could only be reactivated by expansion during parasite mediated polyclonal activation. These studies should facilitate our understanding of the pathogenesis of autoimmune disease following infectious disease. 3) A number of studies have suggested that the pituitary hormone, prolactin (PRL), plays an important role in immunoregulation. We have demonstrated that T cells, B cells, and macrophages express PRL-receptors and that expression of this receptor on T cells is upregulated during the course of T cell activation. No role for maternal PRL could be defined in the development of the immune system, as the thymic abnormalities seen in the offspring of mothers treated with the PRL secretion inhibitor, bromcriptine, did not appear to be secondary to the decreased level of PRL in their offspring. However, T cells from dwarf mice which have a genetic defect in the synthesis of PRL as well as other pituitary hormones were shown to have a defect in their ability to upregulate the expression of the IL-2 receptor following T cell activation in vivo and this defect could be overcome by administration of PRL.

T细胞受体（TCR）的相互作用与其特定配体的相互作用， 肽-MHC，只是事件的一个组成部分 抗原特异性T细胞的激活。 我们学习的主要目标 为了表征细胞表面抗原（共受体）及其可溶性 或相关的配体（反受体），起着关键作用 在细胞 - 细胞相互作用以及T细胞的相互作用中 环境。 我们已经集中精力在许多截然不同的地方 区域：1）我们已经证明了细胞因子白介素10（IL-10）， 通过作用在宏观植物上，而不是其他类型来抑制T细胞激活 辅助单元。 我们进一步阐明了作用机理 IL-10关于抑制巨噬细胞的共刺激活性，并显示 IL-10有选择地抑制B7表达的上调 抗原是T细胞抗原的细胞反受体 CD28。 IL-10对B7表达的调节可能决定 细胞在一代中启动或呈现无反应性 免疫反应。 2）一种免疫耐受性模型涉及 通过注射成年小鼠的诱导外周T细胞消极 葡萄球菌肠毒素。 进一步表征 耐受性T细胞在体内，我们建立了一个体内模型， 生成特定于肠毒素的IL-4产生。这个IL-4途径是 在幼稚的T细胞和T中高度易受耐受性信号 用于IL-4产生的细胞。 耐受的IL-4途径只能 在寄生虫介导的多克隆期间通过膨胀重新激活 激活。 这些研究应该促进我们对 传染病后自身免疫性疾病的发病机理。 3）a 研究数量表明垂体激素催乳素 （PRL），在免疫调节中起重要作用。 我们已经证明了 T细胞，B细胞和巨噬细胞表达PRL受体，并且 该受体在T细胞上的表达在过程中上调 T细胞激活。 在 免疫系统的发展，如胸腺异常 接受PRL分泌抑制剂治疗的母亲的后代， bromcriptine，似乎不是降低的降低 PRL的后代。 但是，来自矮小鼠的T细胞 PRL以及其他垂体激素的合成中的遗传缺陷 被证明具有上调表达的能力缺陷 在体内T细胞激活后的IL-2受体和该缺陷 可以通过PRL给药来克服。