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.
Showing the most recent 10 out of 16 publications
