Loss of Gimap5 promotes pathogenic CD4+ T cell development and allergic airway disease

Publication date: Available online 25 October 2018

Source: Journal of Allergy and Clinical Immunology

Author(s): Andrew R. Patterson, Paige Bolcas, Kristin Lampe, Rachel Cantrell, Brandy Ruff, Ian Lewkowich, Simon P. Hogan, Edith M. Janssen, Jack Bleesing, Gurjit K. Khurana Hershey, Kasper Hoebe

Abstract

Background

The GTPase of immunity-associated protein 5 is essential for lymphocyte homeostasis and survival. Recently, human GIMAP5 SNPs have been linked with an increased risk for asthma, while the loss of Gimap5 in mice has been associated with severe CD4⁺ T cell-driven immune pathology.

Objective

To identify the molecular and cellular mechanisms by which Gimap5-deficiency predisposes to allergic airway disease.

Methods

CD4⁺ T cell polarization and the 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 (HDM)-induced airway inflammation was assessed using a complete Gimap5 LOF (Gimap5^sph/sph) and conditional Gimap5^fl/flCd4^Cre/ert2 mice.

Results

GIMAP5 LOF mutations in both mice and humans are associated with spontaneous polarization towards 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. The DNA damage in Gimap5-deficient CD4⁺ T cells could be controlled by TGFβ, thereby promoting T_H17 polarization. When challenged with HDM 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.

Conclusion

Activation of Gimap5-deficient CD4⁺ T cells is associated with increased DNA damage and reduced survival that can be overcome by TGFβ. This leads to a selective survival of pathogenic T_H17 cells, but also T_H2 in humans and mice, ultimately promoting allergic airway disease.

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