Loss of GTPase of immunity-associated protein 5 (Gimap5) promotes pathogenic CD4⁺ T-cell development and allergic airway disease.

Abstract

GTPase of immunity-associated protein 5 (GIMAP5) is essential for lymphocyte homeostasis and survival. Recently, human GIMAP5 single nucleotide polymorphisms have been linked to an increased risk for asthma, whereas loss of Gimap5 in mice has been associated with severe CD4⁺ T cell-driven immune pathology. We sought to identify the molecular and cellular mechanisms by which Gimap5 deficiency predisposes to allergic airway disease. CD4⁺ T-cell polarization and development of pathogenic CD4⁺ T cells were assessed in Gimap5-deficient mice and a human patient with a GIMAP5 loss-of-function (LOF) mutation. House dust mite-induced airway inflammation was assessed by using a complete Gimap5 LOF (Gimap5^sph/sph) and conditional Gimap5^fl/flCd4^Cre/ert2 mice. GIMAP5 LOF mutations in both mice and human subjects are associated with spontaneous polarization toward pathogenic T_H17 and T_H2 cells in vivo. Mechanistic studies in vitro reveal that impairment of Gimap5-deficient T_H cell differentiation is associated with increased DNA damage, particularly during T_H1-polarizing conditions. DNA damage in Gimap5-deficient CD4⁺ T cells could be controlled by TGF-β, thereby promoting T_H17 polarization. When challenged with house dust mite in vivo, Gimap5-deficient mice displayed an exacerbated asthma phenotype (inflammation and airway hyperresponsiveness), with increased development of T_H2, T_H17, and pathogenic T_H17/T_H2 cells. Activation of Gimap5-deficient CD4⁺ T cells is associated with increased DNA damage and reduced survival that can be overcome by TGF-β. This leads to selective survival of pathogenic T_H17 cells but also T_H2 cells in human subjects and mice, ultimately promoting allergic airway disease.