Increased Mammalian Target of Rapamycin Complex 2 Signaling Promotes Age-Related Decline in CD4 T Cell Signaling and Function

CD4 T cell function declines significantly during aging. Although the mammalian target of rapamycin (TOR) has been implicated in aging, the roles of the TOR complexes (TORC1, TORC2) in the functional declines of CD4 T cells remain unknown. In this study, we demonstrate that aging increases TORC2 signaling in murine CD4 T cells, a change blocked by long-term exposure to rapamycin, suggesting that functional defects may be the result of enhanced TORC2 function. Using overexpression of Rheb to activate TORC1 and Rictor plus Sin1 to augment TORC2 in naive CD4 T cells from young mice, we demonstrated that increased TORC2, but not TORC1, signaling results in aging-associated biochemical changes. Furthermore, elevated TORC2 signaling in naive CD4 T cells from young mice leads to in vivo functional declines. The data presented in this article suggest a novel model in which aging increases TORC2 signaling and leads to CD4 T cell defects in old mice.