Functional characterization of anergic helper T cells

项目总结/摘要 自身免疫性疾病似乎是由危险的非耐受性CD 4 + T细胞引起的， 个人的蛋白质。目前控制这些异常T细胞反应的疗法不能令人满意 因为它们抑制所有的T细胞，包括对病原体和癌细胞有特异性的有用的T细胞。问题 现在摆在面前的领域是如何在CD 4 + T细胞中诱导自身肽特异性免疫耐受， 自身免疫性疾病 危险的CD 4 T细胞中的无反应性诱导和外周调节性T（Treg）细胞扩增代表了两种 持久控制自身免疫性疾病的潜在重要治疗策略。研究在过去的 格兰特时期建立了无反应性自然发生在健康小鼠的多克隆CD 4库中， 与CD 73、FR 4和Nrp 1的上调相关。值得注意的是，无反应性常规Foxp 3-CD 44 hi 还观察到Nrp 1 + FR 4 + CD 73 + CD 4 T细胞分化成功能性Foxp 3 + Treg细胞， 过继转移到Treg缺陷型Tcra-/-宿主中。因此，“无能量源”Treg细胞的发现， 为设计Treg细胞疗法以控制CD 4 T细胞介导的自身免疫提供了新的途径， 抗原特异性方式。 本申请中提出的研究旨在描述许多控制自然无反应性的因素 Treg祖细胞的诱导和产生，包括自身反应性TCR、组织限制性靶向自身免疫反应性T细胞受体（TCRs）、靶向自身免疫反应性T细胞受体（TCRs）和靶向自身免疫反应性T细胞受体（TCRs）。 抗原、致耐受性信号传导事件、CpG DNA去甲基化和无反应性基因表达特征。 此外，所提出的实验将确定如何在细胞内产生无能量来源的Foxp 3 + Treg细胞。 正常宿主并研究其抑制自身免疫性疾病的能力。最后，实验将 建立研究人类无反应性和无反应性来源的Treg细胞的免疫学的可行性。

Project Summary/Abstract Autoimmune diseases appear to be caused by dangerous non-tolerant CD4+ T cells specific for an affected individual's own proteins. Current therapies to control these aberrant T cell responses are unsatisfactory because they inhibit all T cells, including helpful ones specific for pathogens and cancer cells. The question now before the field is how to induce self-peptide specific immunological tolerance in CD4+ T cells that cause autoimmune disease. Anergy induction in dangerous CD4 T cells and peripheral regulatory T (Treg) cell expansion represent two potentially important therapeutic strategies to durably control autoimmune disease. Research during the last grant period established that anergy naturally occurs in the polyclonal CD4 repertoire of healthy mice in association with the up-regulation of CD73, FR4, and Nrp1. Remarkably, anergic conventional Foxp3– CD44hi Nrp1+ FR4+ CD73+ CD4 T cells were also observed to differentiate into functional Foxp3+ Treg cells when adoptively transferred into Treg-deficient Tcra–/– hosts. Therefore, this discovery of `anergy-derived' Treg cells offers a new avenue for the design of Treg cell therapies to control CD4 T cell-mediated autoimmunity in an antigen-specific fashion. Research proposed in this application intends to characterize many of the factors that govern natural anergy induction and the generation of Treg progenitors, including autoreactive TCRs, tissue-restricted target self- antigens, tolerogenic signaling events, CpG DNA de-methylations, and anergic gene expression signatures. Furthermore, proposed experiments will determine how anergy-derived Foxp3+ Treg cells can be generated in normal hosts and investigate their capacity to suppress autoimmune disease. Finally, experiments will establish the feasibility of investigating the immunology of anergy and anergy-derived Treg cells in humans.