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.
Department of Molecular, Cellular, and Developmental Biology, University of Michigan College of Literature, Science and the Arts, Ann Arbor, MI 48109;
Eric
E
Perkey
Diane
D
Fingar
Richard A
RA
Miller
Gonzalo G
GG
Garcia
D000375:Aging; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism; D002478:Cells, Cultured; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020559:Monomeric GTP-Binding Proteins / Q000096:biosynthesis; D046912:Multiprotein Complexes / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D009479:Neuropeptides / Q000096:biosynthesis; D000076205:Ras Homolog Enriched in Brain Protein; D015398:Signal Transduction / Q000276:immunology; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D048868:Adaptor Proteins, Signal Transducing
D002352:Carrier Proteins; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D020559:Monomeric GTP-Binding Proteins; D046912:Multiprotein Complexes; D009479:Neuropeptides; D000076205:Ras Homolog Enriched in Brain Protein; D020123:Sirolimus; D058570:TOR Serine-Threonine Kinases; C490213:Rheb protein, mouse; C561937:Mapkap1 protein, mouse; D048868:Adaptor Proteins, Signal Transducing