Loss of GTPase of immunity-associated protein 5 (Gimap5) promotes pathogenic CD4+ T-cell development and allergic airway disease.
J Allergy Clin Immunol
; 143(1): 245-257.e6, 2019 01.
Article
en En
| MEDLINE
| ID: mdl-30616774
ABSTRACT
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 (Gimap5sph/sph) and conditional Gimap5fl/flCd4Cre/ert2 mice.RESULTS:
GIMAP5 LOF mutations in both mice and human subjects are associated with spontaneous polarization toward pathogenic TH17 and TH2 cells in vivo. Mechanistic studies in vitro reveal that impairment of Gimap5-deficient TH cell differentiation is associated with increased DNA damage, particularly during TH1-polarizing conditions. DNA damage in Gimap5-deficient CD4+ T cells could be controlled by TGF-ß, thereby promoting TH17 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 TH2, TH17, and pathogenic TH17/TH2 cells.CONCLUSION:
Activation of Gimap5-deficient CD4+ T cells is associated with increased DNA damage and reduced survival that can be overcome by TGF-ß. This leads to selective survival of pathogenic TH17 cells but also TH2 cells in human subjects and mice, ultimately promoting allergic airway disease.Palabras clave
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Asma
/
Células Th2
/
Células Th17
/
Mutación con Pérdida de Función
/
GTP Fosfohidrolasas
Tipo de estudio:
Prognostic_studies
/
Risk_factors_studies
Límite:
Animals
/
Humans
Idioma:
En
Revista:
J Allergy Clin Immunol
Año:
2019
Tipo del documento:
Article