Distinct effects of TGF-β1 on CD4+ and CD8+ T cell survival, division, and IL-2 production:: A role for T cell intrinsic Smad3

TGF-beta1 is critical for maintaining T cell homeostasis. Smad3 has been implicated in this regulatory process, yet the cellular targets and molecular details remain poorly understood. In this study, we report that TGF-beta1 impairs the entry of CD4(+) and CD8(+) T cells into the cell cycle as well as their progression through subsequent rounds of division, and show that Smad3 is essential for TGF-beta1 to inhibit TCR-induced division of only CD4(+) and not CD8(+) T cells. Both CD8(+) and CD4(+) T cells from Smad3(-/-) mice were refractory to TGF-beta1-induced inhibition of IL-2 production, thus demonstrating that not all CD8+ T cell responses to TGF-beta1 are Smad3 independent. These TGF-beta1 effects were all T cell intrinsic, as they were reproduced in purified CD4(+) and CD8(+) T cells. Finally, we found that Smad3 was critical for the survival of CD8(+), but not CD4(+) T cells following activation ex vivo. The TCR-induced death of Smad3(-/-) CD8(+) T cells was not dependent upon TNF-alpha production. Exogenous TGF-beta1 partially rescued the CD8(+) T cells by signaling through a Smad3-independent pathway. TGF-beta1 also enhanced survival of TCR-stimulated CD4(+) CD44(high) T cells in a Smad3-independent manner. Collectively, these findings firmly establish for the first time that TGF-beta1 discriminately regulates CD4(+) and CD8(+) T cell expansion by signaling through distinct intracellular pathways.