MTORC1 inhibition pronounces CD8 T cell effector defects in aging (P1233)

Abstract

Abstract Mammalian target of rapamycin complex 1 (mTORC1) is a critical cell nutrient sensor and its role in CD8 T cell development, homeostasis, and fate decisions during infection are becoming increasingly evident. Seminal studies showed that direct mTORC1 inhibition with rapamcyin favored memory CD8 T cell development after infection. Simultaneously, rapamycin was shown to extend lifespan in mice. Whether or not rapamycin treatment alters the CD8 T cell immune response in old mice has not been studied. This question is particularly critical given recent data from our lab that CD8 T cell defects after Listeria monocytogenes (Lm) and West Nile Virus infection are both associated with increased infection mortality in old mice. Therefore, we tested the effect of rapamycin (75μg/kg), when given during the T cell priming phase, on CD8 T cell effector responses in adult (3 months) and old (18 months) mice infected with Lm. We found that mTORC1 inhibition with rapamycin significantly inhibited effector differentiation of antigen-specific CD8 T cells and this was especially pronounced in old mice. Additionally, contrary to previous reports, we measured no benefit on CD8 T cell memory formation in either old or adult mice. Therefore, we conclude that any beneficial effects of rapamycin on memory formation likely come at the cost of effector function, and these effects may be pathogen-specific. Furthermore, rapamycin may not be a suitable candidate for extending lifespan or “Healthspan.”