Survival of CD4+CD25+ Regulatory T Cells

描述(申请人提供)：免疫调节性T细胞(Treg细胞)最近被确认为维持T细胞耐受的一种主动免疫抑制机制。在所描述的几组Treg细胞中，CD4+CD25+Treg细胞占外周CD4+T细胞的5%-10%。在小鼠和人类身上发现的这些细胞，具有强大的免疫调节功能，被认为是“专业的调节性T细胞”。在小鼠模型中，转移CD4+CD25+Treg细胞可以抑制自身免疫性疾病。Treg细胞还参与了抗肿瘤免疫、与移植相关的移植物抗宿主病(GVHD)和抗微生物免疫的调节。因此，CD4+CD25+Treg细胞的存活或死亡可能对免疫动态平衡很重要。尽管CD4+CD25+Treg细胞的产生依赖于CD28，但控制CD4+CD25+Treg细胞存活的机制仍然不清楚。在初步研究中，我们发现了几种不同的Bclx亚型，其中包括一种新的Bclx亚型，它具有独特的C末端，可抑制TCR连接后T细胞的凋亡。这些结果以及其他人的报道进一步表明，CD28共刺激信号可以上调抗凋亡蛋白Bclxl和BclxGamma的表达，提示BclxGamma和Bclxl促进CD3/CD28共连接后T细胞的存活。这一提议将检验这一假设，即CD4+CD25+Treg细胞有一个特定的生存程序，其中Bcl-x基因通过CD28发挥重要作用。推论认为，CD4+CD25+Treg细胞向存活转变，而不是凋亡，可能会导致自身免疫降低，GVHD减少，与抗微生物免疫相关的有害组织损伤减轻。这项建议的主要目的是明确CD4+CD25+Treg细胞的生存计划，特别是Bcl-x基因家族成员的作用。将通过下列具体目标来实现这一目标：(1)通过分析这些基因在CD4+CD25+Treg细胞中的表达和促生存功能，确定这些基因在CD4+CD25+Treg细胞中的功能；(2)确定Bcl-x上调是否与CD4+CD25+Treg细胞的无能状态有关；以及(3)确定通过转导Bcl-x-Gamma和Bcl-xL而从死亡中拯救出来的CD4+CD25+Treg细胞在降低自身免疫性胃炎小鼠模型的免疫病理学中的潜力。对CD4+CD25+Treg细胞存活程序的分子定义可能会通过特别促进Treg细胞的存活来开发针对自身免疫性疾病以及病毒和细菌感染的新治疗策略。

DESCRIPTION (provided by applicant): Immunoregulatory T cells (Treg cells) have recently been identified as an active mechanism of immune suppression for maintaining T cell tolerance. Among several sets of Treg cells described, CD4+CD25+ Treg cells comprise 5-10% of peripheral CD4+ T cells. These cells, identified in mice and humans, exhibit potent immunoregulatory functions and are considered "professional regulatory T cells". In mouse models, transfer of CD4+CD25+ Treg cells can suppress autoimmune diseases. Treg cells have also been implicated in the regulation of anti-tumor immunity, graft-versus-host disease (GVHD) associated with transplantation, and anti-microbial immunity. Thus, the survival or death of CD4+CD25+ Treg cells is likely to be important for immune homeostasis. The mechanisms that govern CD4+CD25+ Treg cell survival remains elusive, although the generation of CD4+CD25+ Treg cells is CD28-dependent. In preliminary studies, several Bcl-x isoforms were identified including a novel Bcl-x isoform, Bcl-x-gamma, which is characterized by a unique C-terminus and inhibits T cell apoptosis after TCR ligation. These results, as well as the reports of others, further showed that CD28 co-stimulatory signals can up-regulate the expression of the anti-apoptotic proteins Bcl-xL and Bcl-x-gamma, suggesting that Bcl-xgamma and Bcl-xL promote T cell survival after CD3/CD28 co-ligation. This proposal will test the hypothesis that CD4+CD25+ Treg cells have a specific survival program in which Bcl-x genes play an important role through CD28. The corollary hypothesis is that a shift toward survival, rather than apoptosis, in CD4+CD25+ Treg cells may lead to reduced autoimmunity, decreased GVHD, and diminished, deleterious tissue damage associated with anti-microbial immunity. The primary goal of this proposal is to define the survival program of CD4+CD25+ Treg cells, and especially the roles of Bcl-x gene family members. This goal will be pursued through the following specific aims: (1) To determine the function of Bcl-x proteins in CD4+CD25+ Treg cells by analysis of the expression and pro-survival function of these genes in the Treg cells; (2) To determine whether Bcl-x up-regulation is responsible for the anergic state of CD4+CD25+ Treg cells; and (3) To determine the potential for CD4+CD25+ Treg cells, rescued from death by transfection with Bcl-x-gamma and Bcl-xL, to reduce the immunopathology in a mouse model of autoimmune gastritis. Molecular definition of the survival program of CD4+CD25+ Treg cells may lead to development of novel therapeutic strategies for autoimmune diseases, as well as viral and bacterial infections by specifically promoting Treg cell survival.