Distinct Effects of TGF-β1 on CD4+ and CD8+ T Cell Survival, Division, and IL-2 Production: A Role for T Cell Intrinsic Smad3

Abstract TGF-β1 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-β1 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-β1 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-β1-induced inhibition of IL-2 production, thus demonstrating that not all CD8+ T cell responses to TGF-β1 are Smad3 independent. These TGF-β1 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-α production. Exogenous TGF-β1 partially rescued the CD8+ T cells by signaling through a Smad3-independent pathway. TGF-β1 also enhanced survival of TCR-stimulated CD4+CD44high T cells in a Smad3-independent manner. Collectively, these findings firmly establish for the first time that TGF-β1 discriminately regulates CD4+ and CD8+ T cell expansion by signaling through distinct intracellular pathways.