An essential role for SREBP signaling in T cell blastogenesis (47.17)

Abstract

Abstract Accumulating evidence indicates that cellular metabolism is an important regulator of T cell immunity. We and others have shown that activation of T cell rapidly initiates a robust genetic and biochemical program that drives the biosynthesis of lipids. Surprisingly, inhibiting lipid synthesis markedly decreases DNA synthesis and lymphocyte proliferation, suggesting a fundamental link between lipid anabolism and cell cycle progression. To date, the molecular mechanisms underlying these intriguing observations are largely undefined. The Sterol Regulatory Element Binding Proteins (SREBP) are b-HLH transcription factors with a well-placed role in lipid homeostasis. The impact of SREBPs on T cell development and function has not been evaluated. Herein we demonstrate an essential role for SREBPs in CD8 T cell blastogenesis. Gene expression and ChIP studies coupled with metabolic flux analysis revealed an essential role for SREBP signaling in the acquisition of a lipid anabolic program by blasting T cells. In the absence of SREBP activity, mitogen-stimulated T cells do not efficiently enlarge and arrest in G0/G1 of cell cycle before undergoing apoptosis-independent cell death. Homeostatic proliferation and antigen-specific viral immunity is also compromised in the absence of SREBP activity. Taken together, these data delineate a critical role for SREBPs in T cell growth and provide a mechanistic understanding of how SREBPs regulate the acquisition of anabolic metabolism in T cells.