Gimap5-dependent inactivation of GSK3β is required for CD4+ T cell homeostasis and prevention of immune pathology

Andrew R. Patterson, Mehari Endale, Kristin Lampe, Halil I. Aksoylar, Aron Flagg, Jim R. Woodgett, David Hildeman, Michael B. Jordan, Harinder Singh, Zeynep Kucuk, Jack Bleesing and Kasper Hoebe ()
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Andrew R. Patterson: Cincinnati Children’s Hospital Research Foundation
Mehari Endale: Cincinnati Children’s Hospital Research Foundation
Kristin Lampe: Cincinnati Children’s Hospital Research Foundation
Halil I. Aksoylar: Harvard T.H. Chan School of Public Health
Aron Flagg: Cleveland Clinic Children’s
Jim R. Woodgett: Mount Sinai Hospital
David Hildeman: Cincinnati Children’s Hospital Research Foundation
Michael B. Jordan: Cincinnati Children’s Hospital Research Foundation
Harinder Singh: Cincinnati Children’s Hospital Research Foundation
Zeynep Kucuk: Cincinnati Children’s Hospital Research Foundation
Jack Bleesing: Cincinnati Children’s Hospital Research Foundation
Kasper Hoebe: Cincinnati Children’s Hospital Research Foundation

Nature Communications, 2018, vol. 9, issue 1, 1-15

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-02897-7

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