Towards understanding the influence of lipid metabolism on CD8 T cell biology (P1136)

Abstract

Abstract A hallmark of the adaptive immune system is the ability of CD8 T cells to undergo rapid clonal expansion in response to antigenic stimulation. To meet the biosynthetic requirements of rapid growth and proliferation, effector T cells must reprogram their metabolism to provide essential macromolecules. We have previously shown that mitogen signaling induces a gene expression program that drives de novo cholesterol and fatty acid biosynthesis, however the molecular events linking antigen receptor signaling with lipid anabolism remain poorly understood. Herein, we demonstrate an essential role for sterol regulatory element binding proteins (SREBPs) in the acquisition of effector cell metabolism. Without SREBP signaling, CD8 T cells are unable to grow and acquire the effector cell metabolism program, resulting in attenuated clonal expansion during viral infection. In contrast, SREBPs are dispensable for homeostatic proliferation, demonstrating a context-specific requirement for SREBP signaling during effector T cell blastogenesis. Mechanistic studies indicate that SREBP activity is required to maintain a level of cellular cholesterol sufficient to permit rapid ER and cellular growth. Taken together, these studies provide novel insights into the molecular signals underlying the metabolic reprogramming of CD8 T cell during the transition from quiescence to activation, and demonstrate the importance of SREBPs in regulating a cholesterol metabolic checkpoint during blastogenesis.