Functional characterization of anergic helper T cells

项目摘要/摘要 自身免疫性疾病似乎是由危险的不可耐受的受影响的CD4+T细胞引起的 个体自身的蛋白质。目前控制这些异常T细胞反应的治疗方法并不令人满意 因为它们抑制所有的T细胞，包括对病原体和癌细胞有帮助的T细胞。问题是 现在之前的领域是如何诱导自体多肽在CD4+T细胞中引起特异性免疫耐受 自身免疫性疾病。 危险的CD4T细胞的无能诱导和外周调节性T(Treg)细胞的扩增代表了两种 可持续控制自身免疫性疾病的潜在重要治疗策略。在过去的几年中进行的研究 授权期确定无能自然地发生在健康小鼠的多克隆CD4谱系中 与CD73、FR4和Nrp1的上调有关。值得注意的是，无能的常规Foxp3-CD44hi 也观察到Nrp1+FR4+CD73+CD4T细胞在以下情况下分化为具有功能的Foxp3+Treg细胞 过继转移到Treg缺陷的TCRA-/-宿主。因此，“无能”来源的Treg细胞的这一发现 为设计Treg细胞疗法控制CD4T细胞介导的自身免疫提供了一条新的途径 特定于抗原的时尚。 本申请中提出的研究意在描述控制自然无能的许多因素。 Treg祖细胞的诱导和生成，包括自身反应性TCR、组织限制性靶向自身 抗原、耐受信号事件、CpG DNA去甲基化和无能基因表达特征。 此外，拟议的实验将确定无能来源的Foxp3+Treg细胞如何在 并研究它们抑制自身免疫性疾病的能力。最后，实验将 建立研究人类无能和无能来源的Treg细胞免疫学的可行性。

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.