RECEPTORS, CORECEPTORS, AND COUNTER RECEPTORS FOR T CELL ACTIVATION

T 细胞激活的受体、辅助受体和反受体

• 批准号: 6098889
• 负责人: ETHAN 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/6098889
• 关键词: CD28 molecule; CD3 molecule; CD40 molecule; T cell receptor; T lymphocyte; biological signal transduction; cell cell interaction; cell differentiation; gene expression; hamsters; human tissue; integrins; laboratory mouse; laboratory rat; leukocyte activation /transformation; major histocompatibility complex; monoclonal antibody; surface antigens; thymus; tissue /cell culture

The major goal of this project is to further our understanding of the role of regulatory T cells in preventing autoimmunity. Organ-specific autoimmune disease develops in certain strains of mice following thymectomy on day 3 of life (d3TX). This disease process is mediated by CD4+ T cells and can be transferred to immunodeficient mice by CD4+ T cells. CD4+ T cells from euthymic animals can inhibit the development of disease when transferred into the d3Tx animals before 14 days of age. It is therefore likely that regulatory T cells whose development is prevented by thymectomy are responsible for preventing autoimmunity throughout the life span of the animal. We have focused our efforts on the characterization of the autoimmune effector cells responsible for the pathogenesis of the disease and on the suppressor/regulatory cells which control the activity of disease inducing effector cells. It has been demonstrated recently that the regulatory CD4+ T cell that prevent disease co-express CD25. We have further characterized the population of CD4+CD25+ immunoregulatory cells and demonstrated that they can suppress not only the induction of disease post-thymectomy, but can also suppress disease induced by cloned autoantigen specific effector cells. Furthermore, the CD4+CD25+ cells appear to be members of unique lineage of regulatory cells, as the induction of CD25 expression on a mono- specific population of T cells derived from TCR-transgenic SCID mice did not result in suppression of post-thymectomy autoimmunity. In addition, the TCR transgenic SCID mice were highly susceptible to autoimmune disease induced by cloned lines of autoantigen-specific effectors, while normal mice were relatively resistant. The capacity of the cloned line to transfer disease to nu/nu recipients could be inhibited by normal spleen cell populations containing CD4+CD25+ and by purified CD4+ CD25+ T cells. One of the major problems in the analysis of the pathogenesis of any model of spontaneous organ specific autoimmunity is the identification of the initiating antigen. We have defined the target antigen responsible for the pathogenesis of autoimmune gastritis in d3Tx BALB/c mouse as the proton pump, H/K ATPase, of the gastric parietal cell. Freshly explanted gastric LN cells from d3Tx mice react significantly to the H/K ATPase a-chain, but only marginally to the b-chain. Two H/K ATPAse reactive T cell lines were derived from the gastric LN of d3Tx mice. Both were CD4+, TCR a/b+ and recognized two distinct peptides derived from the a-chain in association with I-Ad. One cell line secreted Th1 and the other Th2 cytokines, but both were equally potent inducers of gastritis with distinct profiles of cellular infilration in nu/nu recipent animals. Neither of the cell lines induced disease in normal BALB/C animals and transfer of disease to nu/nu recipients was blocked by cotransfer of normal BALB/c spleen cells containing CD25+ cells. Our demonstration that the pathogenic activity in vivo of both activated Th1/Th2 lines can be abrogated by cotransfer of CD4+CD25+ cells, strongly suggests that the regulatory T cell population may have a therapeutic role in other models of established autoimmunity. Although these studies offer strong evidence for the existence of a population of CD4+CD25+immmunoregulatory T cells in vivo, the activity of these suppressor populations has been measured in systems that require weeks to months of assessment of disease activity. It has therefore proven difficult to determine their mechanism of action, their antigen specificity, or their cellular targets. To analyze the mechanism of action of the CD4+CD25+ cells, we have established an in vitro model system that mimics the function of these cells in vivo. Purified CD4+CD25+ cells failed to proliferate following stimulation with IL-2 alone of through the TCR. When co-cultured with CD4+CD25- cells, the CD4+ CD25+ cells markedly suppressed proliferation by specifically inhibiting the production of IL-2. The inhibition was not cytokine mediated, was dependent on cell contact between the regulatory cells and the responders, and required activation of the suppressors via the TCR. Inhibition could be overcome by the addition to the cultures of IL-2 or anti-CD28, suggesting that the CD4+CD25+ cells may function by blocking the delivery of a costimulatory signal. Induction of CD25 expression on CD25- negative T cells in vitro or in vivo did not result in the generation of suppressor activity. Collectively, these studies support the concept that CD4+CD25+ T cells in normal mice may represent a distinct lineage of professional suppressor cells.

该项目的主要目标是进一步 了解调节性T细胞在预防中的作用 自身免疫性。器官特异性自身免疫性疾病在 胸腺切除术后第3天的某些小鼠菌株 （D3TX）。此疾病过程是由CD4+ T细胞介导的，可以 通过CD4+ T细胞转移到免疫缺陷的小鼠中。 CD4+ t 来自正式动物的细胞可以抑制疾病的发展 当14天之前转移到D3TX动物中时。这是 因此，可能是其发育的调节T细胞 胸腺切除术预防 在动物的整个生命周期中自身免疫。我们有 将我们的精力集中在自身免疫的表征上 效应细胞负责疾病的发病机理和 控制疾病活性的抑制/调节细胞 诱导效应细胞。最近已经证明了 预防疾病共表达CD25的调节性CD4+ T细胞。我们 进一步表征了CD4+CD25+的种群 免疫调节细胞，并证明它们可以抑制 不仅诱导疾病后心房切除术，而且还可以 抑制克隆自身抗原特异性效应子引起的疾病 细胞。此外，CD4+ CD25+细胞似乎是 调节细胞的独特谱系，作为CD25的诱导 在源自T细胞的单特异性群体上的表达 TCR-转基因SCID小鼠不会导致抑制 术后自身免疫性。另外，TCR转基因 SCID小鼠非常容易受到自身免疫性疾病的影响 通过自身抗原特异性效应子的克隆线，而正常小鼠 相对抗性。克隆线转移的能力 正常脾细胞可以抑制对NU/NU接受者的疾病 包含CD4+ CD25+的种群和纯化的CD4+ CD25+ T细胞。分析的主要问题之一 任何自发器官特异性模型的发病机理 自身免疫性是对抗原的识别。我们有 定义了负责发病机理的靶抗原 D3TX BALB/C小鼠中的自身免疫性胃炎作为质子泵， 胃顶细胞的H/K ATPase。刚植入的胃 来自D3TX小鼠的LN细胞对H/K ATPase的反应显着反应 a链，但仅略偏向B链。两个H/K ATPase 反应性T细胞系来自D3TX小鼠的胃LN。 两者都是CD4+，TCR A/B+，并识别出两个不同的肽 源自与I-AD的A链。一个单元线 分泌的Th1和其他TH2细胞因子，但两者均相同 具有不同细胞曲线的胃炎的有效诱导剂 NU/NU接受者动物中的浸润。细胞系都不 正常BALB/C动物诱导疾病和疾病转移 正常BALB/C的共转移阻止了NU/NU接收者 包含CD25+细胞的脾细胞。我们的演示表明 两种激活的Th1/Th2线的体内致病活性可以是 通过CD4+ CD25+细胞的共转移废除，强烈建议 调节性T细胞种群可能在 其他已建立自身免疫性的模型。虽然这些研究 提供有力的证据证明存在 CD4+CD25+Immunoregulatory T细胞体内， 这些抑制剂种群已经在系统中测量 需要数周到几个月的疾病活动评估。它有 因此被证明很难确定其作用机理， 它们的抗原特异性或细胞靶标。分析 CD4+ CD25+细胞的作用机理，我们已经建立了 一个模拟这些细胞功能的体外模型系统 体内。纯化的CD4+ CD25+细胞无法增殖 单独使用IL-2通过TCR刺激。共培养时 与CD4+ CD25细胞，CD4+ CD25+细胞明显 通过特别抑制产生的生产来抑制增殖 IL-2。抑制不是介导的细胞因子，取决于 调节细胞与响应者之间的细胞接触，以及 需要通过TCR激活抑制器。抑制可能 通过增加IL-2或抗CD28的培养物来克服 表明CD4+ CD25+细胞可能通过阻止 传递共刺激信号。诱导CD25表达在 CD25-体外或体内的负T细胞不会导致 产生抑制活性。总的来说，这些研究 支持正常小鼠中CD4+ CD25+ T细胞的概念 代表专业抑制细胞的独特谱系。