TGF-β Signalling Is Required for CD4+ T Cell Homeostasis But Dispensable for Regulatory T Cell Function

Tgf-β is widely held to be critical for the maintenance and function of regulatory t (treg) cells and thus peripheral tolerance. this is highlighted by constitutive ablation of tgf-β receptor (tr) during thymic development in mice,which leads to a lethal autoimmune syndrome. here we describe that tgf-β-driven peripheral tolerance is not regulated by tgf-β signalling on mature cd4+ t cells. inducible tr2 ablation specifically on cd4+ t cells did not result in a lethal autoinflammation. transfer of these tr2-deficient cd4+ t cells to lymphopenic recipients resulted in colitis,but not overt autoimmunity. in contrast,thymic ablation of tr2 in combination with lymphopenia led to lethal multi-organ inflammation. interestingly,deletion of tr2 on mature cd4+ t cells does not result in the collapse of the treg cell population as observed in constitutive models. instead,a pronounced enlargement of both regulatory and effector memory t cell pools was observed. this expansion is cell-intrinsic and seems to be caused by increased t cell receptor sensitivity independently of common gamma chain-dependent cytokine signals. the expression of foxp3 and other regulatory t cells markers was not dependent on tgf-β signalling and the tr2-deficient treg cells retained their suppressive function both in vitro and in vivo. in summary,absence of tgf-β signalling on mature cd4+ t cells is not responsible for breakdown of peripheral tolerance,but rather controls homeostasis of mature t cells in adult mice. © 2013 śledzińska et al.