Inositol polyphosphate multikinase regulates Th1 and Th17 cell differentiation by controlling Akt-mTOR signaling

Abstract

Activated proinflammatory T helper (Th) cells, such as Th1 and Th17 cells, mediate immune responses against intra- and extra-cellular pathogens as well as cause the development of various autoimmune diseases. Inositol polyphosphate multikinase (IPMK) is a key enzyme essential for inositol phosphate and phosphoinositide metabolism, which is known to control major biological events such as growth; however, its role in the function of Th cells remains unclear. Here we show that the expression of IPMK is highly induced in distinct Th1 and Th17 subsets. Further, while conditional deletion of IPMK in CD4+ T cells is dispensable for Th2-dependent immune responses, both Th1- and Th17-mediated immune responses are markedly diminished when this enzyme is absent resulting in reduced resistance to Leishmania major infection and attenuation of experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis. In addition, IPMK-deficient naive CD4+ T cells display aberrant T cell activation and impaired differentiation into Th17 cells, which is associated with reduced activation of Akt, mechanistic target of rapamycin (mTOR), and STAT3. Mechanistically, IPMK as a phosphatidylinositol 3-kinase (PI3-kinase) controls the production of phosphatidylinositol (3,4,5)-trisphosphate, thereby promoting T cell activation, differentiation, and effector functions. Our findings suggest that IPMK acts as a critical regulator of Th1 and Th17 differentiation, highlighting the physiological importance of IPMK in Th1- and Th17-mediated immune homeostasis.