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

Background 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. Objective We sought to identify the molecular and cellular mechanisms by which Gimap5 deficiency predisposes to allergic airway disease. Methods 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/fl Cd4 Cre/ert2 mice. Results GIMAP5 LOF mutations in both mice and human subjects are associated with spontaneous polarization toward pathogenic T H 17 and T H 2 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 H 1-polarizing conditions. DNA damage in Gimap5-deficient CD4 + T cells could be controlled by TGF-β, thereby promoting T H 17 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 H 2, T H 17, and pathogenic T H 17/T H 2 cells. Conclusion 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 H 17 cells but also T H 2 cells in human subjects and mice, ultimately promoting allergic airway disease.