Gimap5-dependent inactivation of GSK3 is required for CD4 T cell homeostasis and prevention of immune pathology

Abstract

Abstract The GTPase of immunity-associated protein 5 (Gimap5) has been linked with lymphocyte survival, autoimmunity and colitis development. Previous studies indicated that Gimap5-deficient mice exhibit a reduced lymphocyte proliferation and survival. Here we show that Gimap5 is essential for inactivation of Glycogen Synthase Kinase-3β (GSK3β) following T cell activation, a constitutive active Ser/Thr kinase whose activity reduces β-catenin and c-Myc levels thereby maintaining T cell quiescence. Gimap5 regulates the subcellular localization of GSK3β and its phosphorylation at Ser389, which limits DNA damage during T cell proliferation. Importantly, pharmacologic and genetic targeting of GSK3 in mice can override Gimap5-deficiency in CD4+ T cells, preventing exacerbated DNA damage while enhancing T cell proliferation and survival. Additionally, this ameliorates immune-mediated pathology in vivo. Finally, we show that a human patient carrying a GIMAP5 loss-of-function mutation exhibits similar T cell defects and pathologies and exhibit a reduced T cell proliferation and survival associated with increased DNA damage that can be corrected in vitro with GSK3 inhibitors. T cells require a robust clonal expansion during an effective immune response. Given the predominant expression of GIMAP5 in lymphocytes, we propose that the identified pathway presents a novel and critical molecular mechanism required for productive CD4+ T cell responses and immune homeostasis in the periphery.