TGF-β inhibits IL-7-induced proliferation in memory but not naive human CD4+ T cells

TGF-beta is a potent suppressor of T cell activation and expansion. Although the antiproliferative effects of TGF-beta are well characterized in TCR-activated cells, the effects of TGF-beta on T cell proliferation driven by homeostatic cytokines, such as IL-7, are poorly defined. In the current study, we found that TGF-beta inhibits IL-7-induced proliferation in memory, but not in naive human CD4(+) T cells. TGF-beta impaired c-myc induction in all CD4(+) T cell maturation subsets, although the impairment was less sustained in naive CD4(+) T cells. TGF-beta had no discernible effect on IL-7R signaling (p-STAT-5, p-Akt, or p-S6) in memory T cells but selectively enhanced p-S6 signaling in naive T cells. The inhibitory effects of TGF-beta on memory T cell proliferation were partially overcome by chemical inhibition of GSK-3, which also led to enhanced c-myc expression. These data suggest that TGF-beta could play an important role in limiting homeostatic proliferation of memory T cells. Our observations also point toward a novel strategy to subvert TGF-beta-mediated inhibition of memory T cells by targeting GSK-3 for inhibition.