The control of CD4+CD25+Foxp3+ regulatory T cell survival

CD4(+)CD25(+)Foxp3(+) regulatory T (T-reg) cells are believed to play an important role in suppressing autoimmunity and maintaining peripheral tolerance. How their survival is regulated in the periphery is less clear. Here we show that T-reg cells express receptors for gamma chain cytokines and are dependent on an exogenous supply of these cytokines to overcome cytokine withdrawal apoptosis in vitro. This result was validated in vivo by the accumulation of T-reg cells in Bim(-/-) and Bcl-2 tg mice which have arrested cytokine deprivation apoptosis. We also found that CD25 and Foxp3 expression were down-regulated in the absence of these cytokines. CD25(+) cells from Scurfy mice do not depend on cytokines for survival demonstrating that Foxp3 increases their dependence on cytokines by suppressing cytokine production in T-reg cells. Our study reveals that the survival of T-reg cells is strictly dependent on cytokines and cytokine producing cells because they do not produce cytokines. Our study thus, demonstrates that different gamma chain cytokines regulate T-reg homeostasis in the periphery by differentially regulating survival and proliferation. These findings may shed light on ways to manipulate T-reg cells that could be utilized for their therapeutic applications.