TGF-? signalling is required for CD4? T cell homeostasis but dispensable for regulatory T cell function.

TGF-? is widely held to be critical for the maintenance and function of regulatory T (T(reg)) cells and thus peripheral tolerance. This is highlighted by constitutive ablation of TGF-? receptor (TR) during thymic development in mice, which leads to a lethal autoimmune syndrome. Here we describe that TGF-?-driven peripheral tolerance is not regulated by TGF-? 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 T(reg) 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-? signalling and the TR2-deficient T(reg) cells retained their suppressive function both in vitro and in vivo. In summary, absence of TGF-? 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.     «

TGF-? is widely held to be critical for the maintenance and function of regulatory T (T(reg)) cells and thus peripheral tolerance. This is highlighted by constitutive ablation of TGF-? receptor (TR) during thymic development in mice, which leads to a lethal autoimmune syndrome. Here we describe that TGF-?-driven peripheral tolerance is not regulated by TGF-? signalling on mature CD4? T cells. Inducible TR2 ablation specifically on CD4? T cells did not result in a lethal autoinflammation. Transfe...     »