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

Nat Commun. 2018 Jan 30;9(1):430. doi: 10.1038/s41467-018-02897-7.

Andrew R Patterson ¹ ², Mehari Endale ³, Kristin Lampe ¹, Halil I Aksoylar ⁴, Aron Flagg ⁵, Jim R Woodgett ⁶, David Hildeman ¹ ², Michael B Jordan ¹ ², Harinder Singh ¹ ², Zeynep Kucuk ⁷, Jack Bleesing ⁷, Kasper Hoebe ⁸ ⁹ ¹⁰

Affiliations

1 Division of Immunobiology, Cincinnati Children's Hospital Research Foundation, 3333 Burnet Avenue, Cincinnati, OH, 45229, USA.
2 Immunology Graduate Program, Cincinnati Children's Hospital Medical Center and the University of Cincinnati College of Medicine, 231 Albert Sabin Way # E251n, Cincinnati, OH, 45267, USA.
3 Division of Neonatology and Pulmonary Biology, Cincinnati Children's Hospital Research Foundation, 3333 Burnet Avenue, Cincinnati, OH, 45229, USA.
4 Department of Genetics and Complex Diseases, Harvard T.H. Chan School of Public Health, 677 Huntington Avenue, Boston, MA, 02115, USA.
5 Pediatric Hematology/Oncology and Blood & Marrow Transplant, Cleveland Clinic Children's, 9500 Euclid Avenue, Cleveland, OH, 44195, USA.
6 The Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, 600 University Avenue, Toronto, ON, M5G 1X5, Canada.
7 Division of Bone Marrow Transplantation & Immune Deficiency, Cincinnati Children's Hospital Research Foundation, 3333 Burnet Avenue, Cincinnati, OH, 45229, USA.
8 Division of Immunobiology, Cincinnati Children's Hospital Research Foundation, 3333 Burnet Avenue, Cincinnati, OH, 45229, USA. kasper.hoebe@cchmc.org.
9 Immunology Graduate Program, Cincinnati Children's Hospital Medical Center and the University of Cincinnati College of Medicine, 231 Albert Sabin Way # E251n, Cincinnati, OH, 45267, USA. kasper.hoebe@cchmc.org.
10 Department of Pediatrics, University of Cincinnati, College of Medicine, 3230 Eden Avenue, Cincinnati, OH, 45267, USA. kasper.hoebe@cchmc.org.

PMID: 29382851 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.

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