Rag GTPase critically contributes to humoral immunity independent of canonical mTORC1 signaling

Abstract

Abstract The humoral immune response requires that B cells undergo a rapid metabolic shift and high demand of nutrients, which are vital to sustain the formation of germinal center. Rag GTPase senses amino acid availability to activate mechanistic target of rapamycin complex 1(mTORC1) pathway and modulate the function of transcription factor EB (TFEB), a member of the microphthalmia (MiT/TFE) family of HLH-leucine zipper transcription factors. However, little is known about how Rag GTPase coordinates amino acid sensing, mTORC1 activation and TFEB activity in humoral immune response. Here, we show that B cell intrinsic Rag GTPase is critical to the development and activation of B cells. Disruption of Rag GTPase complex, but not mTORC1 complex, abrogates germinal center formation, antibody production as well as plasma cell generation upon respiratory influenza infection. Mechanistically, the Rag GTPase complex senses specific amino acids to suppress TFEB activity, independent of canonical mTORC1 activation. Collectively, our data support the idea that Rag GTPase critically contributes to humoral immunity partly through suppressing TFEB and it is largely not necessary for canonical mTORC1 signaling. Supported by Mayo Foundation for Medical Education and Research