Identification of roles of inositol polyphosphate metabolism in the regulation of functions and differentiation of CD4 helper T cells

Abstract

Inositol polyphosphate multikinase (IPMK) physiologically creates IP4 and IP5. IPMK is also known as an important phosphatidylinositol 3 kinase (PI3K) that forms PIP3 which activates Akt and influences cell growth. Whereas actions of classical PI3K enzymes are well-identified in lymphocytes, there are no reports to study whether IPMK is involved in diverse steps of CD4+ T cell biology. I first identified that the expression level of IPMK is highly induced in a distinct Th17 subset. Also, production of IL-17A under Th17 differentiation condition are highly attenuated in IPMK-/-CD4+ T cells relative to control cells. In in vivo EAE model, IPMK deficiency in T cells showed attenuated clinical outcome, indicating reduced Th17 immune response. Transcriptional profiles have revealed IPMK-/-CD4+ T cells show marked increase of Foxp3 gene under Th17 differentiation condition. I identified IPMK regulates phosphorylation of STAT3 activated IL-6 receptor signaling via socs3 inhibition. Thus, the finding of this study is the specific molecular mechanism of IPMK signaling actions in CD4+ T cells in distinct types of Th17 cells.Inositol pyrophosphates 5-IP7, formed by inositol hexakisphosphate kinases (IP6Ks), are highly energetic inositol metabolites. 5-IP7 is a physiological inhibitor of AKT, preventing translocation of AKT to the membrane. Whereas action of IP6K1 are well-known in innate immune cells, neutrophils, there are no research about adaptive immune system like CD4+ T cells. Here, I assessed that IP6K1 protein was highly expressed in CD4+ T cells 48 hours after TCR stimulation. Surprisingly, IP6K1-/-CD4+ T cells showed increase of apoptotic cell death at a late phase of TCR stimulation. Furthermore, IP6K1-/-CD4+ T cells displayed attenuated phosphorylation of AKT unlike previous reporting. Transcription factor inducing apoptosis, c-Jun, was enhanced in IP6K1-deficient CD4+ T cells at a late stage of TCR stimulation. IP6K1 has, therefore, a role for cellular survival signaling in CD4+ helper T cells.