Gimap5-dependent inactivation of GSK3\u03b2 is required for CD4+ T cell homeostasis and prevention of immune pathology

Andrew R Patterson,Jack Bleesing,Kristin Lampe,Jim R Woodgett,David Hildeman,Harinder Singh,Zeynep Kucuk,Michael B Jordan,Kasper Hoebe,Mehari Endale,Aron Flagg,Halil I Aksoylar

doi:10.1038/s41467-018-02897-7

Abstract

GTPase of immunity-associated protein 5 (Gimap5) is linked with lymphocyte survival, autoimmunity, and colitis, but its mechanisms of action are unclear. Here, we show that Gimap5 is essential for the inactivation of glycogen synthase kinase-3β (GSK3β) following T cell activation. In the absence of Gimap5, constitutive GSK3β activity constrains c-Myc induction and NFATc1 nuclear import, thereby limiting productive CD4+ T cell proliferation. Additionally, Gimap5 facilitates Ser389 phosphorylation and nuclear translocation of GSK3β, thereby limiting DNA damage in CD4+ T cells. Importantly, pharmacological inhibition and genetic targeting of GSK3β can override Gimap5 deficiency in CD4+ T cells and ameliorates immunopathology in mice. Finally, we show that a human patient with a GIMAP5 loss-of-function mutation has lymphopenia and impaired T cell proliferation in vitro that can be rescued with GSK3 inhibitors. Given that the expression of Gimap5 is lymphocyte-restricted, we propose that its control of GSK3β is an important checkpoint in lymphocyte proliferation.

Highlights

GTPase of immunity-associated protein 5 (Gimap5) is linked with lymphocyte survival, autoimmunity, and colitis, but its mechanisms of action are unclear
To determine whether the observed reduction in peripheral CD4+ T cells might stem from abnormal thymic CD4+ T cell development, we investigated whether the survival and/or output of thymic CD4+ T cells in Gimap5sph/sph mice was affected
Our data indicate no differences in the survival ex vivo between single positive (SP) CD4+ thymocytes isolated from wildtype (WT) and Gimap5sph/sph mice (Supplementary Figure 1A)

Summary

Introduction

GTPase of immunity-associated protein 5 (Gimap5) is linked with lymphocyte survival, autoimmunity, and colitis, but its mechanisms of action are unclear. Mice and rats with complete loss-of-function (LOF) mutations have reduced lymphocyte survival, loss of immunological tolerance predisposing to autoimmunity and colitis, and abnormal liver pathology resulting from persistent post-natal extramedullary hematopoiesis[5,6,7,8,9,10,11,12,13,14] Despite this critical role of Gimap[5] in lymphocyte survival and peripheral tolerance, the underlying mechanism(s) are unclear. Gimap5sph/sph mice progressively lose CD4+ T cells and B cells, an effect that is associated with reduced regulatory T (Treg) cell function, while remaining CD4+ T cells have an activated phenotype, but have an impaired capacity to proliferate[5,6] These immunologic defects result in spontaneous and lethal colitis that is preventable with CD4+ T cell depletion, Treg cell transplantation, or antibiotic therapy[5,6]. Gimap[5] is a critical inhibitor of GSK3β in both human and mouse CD4+ T cells, affecting c-Myc and Mcl-1 expression, NFATc1 nuclear translocation, and T cell fitness by controlling the DNA damage response occurring during T cell proliferation

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