Survival of CD4+CD25+ Regulatory T Cells

描述（由申请人提供）：免疫调节性T细胞（Treg细胞）最近被鉴定为维持T细胞耐受性的免疫抑制活性机制。在所述的几组Treg细胞中，CD 4 + CD 25 + Treg细胞占外周CD 4 + T细胞的5-10%。在小鼠和人类中鉴定的这些细胞表现出有效的免疫调节功能，被认为是“专业调节性T细胞”。在小鼠模型中，CD 4 + CD 25 + Treg细胞的转移可以抑制自身免疫性疾病。Treg细胞还涉及抗肿瘤免疫、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，CD 4 + CD 25 + Treg细胞的存活或死亡对于免疫稳态可能是重要的。尽管CD 4 + CD 25 + Treg细胞的产生是CD 28依赖性的，但控制CD 4 + CD 25 + Treg细胞存活的机制仍然难以捉摸。在初步研究中，鉴定了几种Bcl-x同种型，包括新的Bcl-x同种型Bcl-x-γ，其特征在于独特的C末端并在TCR连接后抑制T细胞凋亡。这些结果以及其他人的报道进一步表明，CD 28共刺激信号可以上调抗凋亡蛋白Bcl-xL和Bcl-x-γ的表达，表明Bcl-x-γ和Bcl-xL促进CD 3/CD 28共连接后的T细胞存活。该提案将检验CD 4 + CD 25 + Treg细胞具有特定存活程序的假设，其中Bcl-x基因通过CD 28发挥重要作用。推论假设是，CD 4 + CD 25 + Treg细胞向存活而不是凋亡的转变可能导致自身免疫性降低、GVHD减少以及与抗微生物免疫相关的有害组织损伤减少。该提案的主要目标是确定CD 4 + CD 25 + Treg细胞的存活程序，特别是Bcl-x基因家族成员的作用。本研究的主要目的是：（1）通过分析Bcl-x蛋白在CD 4 + CD 25 + Treg细胞中的表达及其促生存功能，确定Bcl-x蛋白在Treg细胞中的功能;（2）确定Bcl-x蛋白的上调是否是导致CD 4 + CD 25 + Treg细胞无能的原因;以及（3）确定通过用Bcl-x-γ和Bcl-xL转染而从死亡中拯救的CD 4 + CD 25 + Treg细胞减少自身免疫性胃炎小鼠模型中的免疫病理学的潜力。对CD 4 + CD 25 + Treg细胞存活程序的分子定义可能会导致开发通过特异性促进Treg细胞存活来治疗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.