TAPP adaptors control Akt-dependent metabolic activation of germinal center B cells and suppress autoimmunity via binding to the SHIP product PI(3,4)P2

Abstract

Abstract The phosphoinositide phosphatase SHIP regulates B cell activation by converting the PI 3-kinase product PI(3,4,5)P3 to PI(3,4)P2. While this activity of SHIP appears critical for generation of effective adaptive immunity while avoiding autoimmunity, the function of PI(3,4)P2 in B cells remains relatively unexplored. Tandem PH domain containing proteins (TAPPs) are adaptor proteins that specifically bind to PI(3,4)P2 via their C-terminal PH domains, targeting them to the plasma membrane. Mice bearing inactivating mutations in the PH domains of both TAPP1 and TAPP2, uncoupling them from PI(3,4)P2, exhibit hypergammaglobulinemia and develop lupus-like characteristics including anti-DNA antibodies and deposition of immune complexes in kidneys. Here we find that TAPP KI mice develop chronic germinal centres (GCs) and age-associated increases in B cell expression of activation, exhaustion and memory markers, all of which are B cell intrinsic and dependent on the co-stimulatory molecule ICOS. TAPP KI B cells exhibit elevated phosphorylation of Akt and its target GSK3, and increased survival. Strikingly, TAPP KI B cells exhibit increased metabolic activity associated with elevated oxygen consumption rate, increased extracellular acidification rate, increased expression of glucose transporter Glut1 and increased glucose transport rate. Together our findings suggest that TAPP-PI(3,4)P2 interaction is important for regulating signalling via Akt, B cell metabolism and development of autoimmunity.