Mitochondrial Glycerol‐3‐Phosphate Acyltransferase 1 Regulates T‐lymphocyte Proliferation

Abstract

Mitochondrial glycerol-3-phosphate acyltransferase (mtGPAT) is important in the de novo synthesis of all cellular glycerophospholipids. We have previously shown that T-lymphocytes express mtGPAT1, but not mtGPAT2, and that suppressed proliferation correlates with reduced mtGPAT1 activity in aged T-lymphocytes. To establish a cause/effect relationship between mtGPAT1 and T-lymphocyte proliferation, we examined T-lymphocyte function in mtGPAT1 knockout mice. Splenic T-lymphocyte proliferation in response to CD3 and CD28 receptor stimulation was significantly reduced in the knockout mice. In contrast, stimulation with PMA and ionomycin had no significant effect in knockout compared to wild type mice. Lipid analysis shows that knockout mice have significantly reduced levels of all glycerophospholipid classes tested while sphingomyelin and cholesterol mass was not affected in splenic T-lymphocytes. Similar effects on glycerophospholipid mass were seen in thymocytes from knockout mice. Thymus weight was significantly reduced and there was an increase in double-negative thymocytes and a concomitant decrease in double positive thymocytes in knockout mice. Taken together, these data provide insight into a novel mechanism by which lipid metabolism may regulate T-lymphocyte development and subsequent proliferation in the periphery. This work was supported by NIH AG20651 (CAJ).