W103 - IRF5 Regulation of CD4+ T Cell Metabolism Controls CD40L Expression

Systemic Lupus Erythematosus (SLE) is a devastating autoimmune disease that results from failure of the immune system to distinguish “self” from “non-self”. Studies in our lab and others demonstrated that human SLE CD4+ T cells have elevated levels of IRF5 and increased metabolism, while Irf5 knockout murine CD4+ T cells show diminished oxidative phosphorylation and glycolysis. However, how IRF5 contributes to CD4+ T cell support of B cell function and dysfunction has not been fully elucidated. Using IRF5 KO C57BL/6J mice, we show that loss of IRF5 in CD4+ T cells directly contributes to defects in plasmablast generation. Examination of the CD40-CD40L interaction revealed significant decreases in CD40L expression in Irf5 KO T cells. Analysis of Cd40lg transcript expression showed no difference in mRNA expression in Irf5 KO CD4+ T cells. This finding indicated a novel post-transcriptional regulatory role for IRF5. Examination of the canonical mTOR pathway, a key translational regulator, showed decreased phosphorylation of the S6 ribosomal protein with loss of Irf5, indicating diminished activity of the mTOR pathway. mTOR inhibition with rapamycin in turn resulted in decreased CD40L expression, supporting a role for mTOR in CD40L regulation. As mTOR signaling is known to be regulated by metabolism, we examined if loss of IRF5 resulted in altered T cell metabolism. We found that Irf5 KO T cells have decreased glucose metabolism and increased glutamine metabolism. This data has increased our understanding of how metabolism influences CD4+ T cell function and provides insight into novel post-translational regulatory roles for IRF5.