Metabolic regulation of follicular helper T cell differentiation in a mouse model of lupus

Follicular helper T (T_FH) cells are expanded in systemic lupus erythematosus (SLE), where they are required for production of high affinity autoantibodies. A better understanding of the mechanisms that regulate the differentiation of T_FH cells is critical. Naïve T cells from lupus-prone B6.NZM2410.Sle1.Sle2.Sle3 (TC) mice showed an intrinsic higher capacity to differentiate into T_FH cells. Metabolic reprogramming is a vital regulatory mechanism for T cell differentiation, but how metabolic pathways contribute to T_FH cell expansion in SLE remains elusive. Here we show that glycolysis, mTOR signaling, FAO, and the activity of complex V of the electron transport chain support T_FH lineage commitment. Blocking complex I uniquely decreased the expansion of T_FH cells from lupus-prone mice, and inhibition of some pathways had a greater effect in lupus-prone than control T_FH cells. However, blocking glutaminolysis, complex III and ADP/ATP translocase did not affect T_FH cell expansion. Together, our results identified novel intrinsic metabolic requirements for T_FH cell differentiation, and further defined the differential metabolic pathways that support the expansion of T_FH cells in lupus-prone mice. Together, our data indicates the crucial but distinct roles for metabolic pathways in T_FH cell differentiation and provide a comprehensive experimental basis for fully understanding the precise roles of distant metabolic signaling in regulating the T_FH cell differentiation.