T cells regulate interstitial lung disease via expression of integrins (95.9)

Abstract

Abstract Interstitial lung disease, a combination of pulmonary inflammation and fibrosis, is deadly and occurs idiopathically or as a complication of autoimmune rheumatic diseases (scleroderma, rheumatoid arthritis, poly- and dermatomyositis, lupus). T cells often accumulate in the lungs of such patients. Previous reports suggested that αV-containing integrins may activate TGF-β and facilitate fibrosis. Whether pulmonary T cells utilize such integrins in interstitial lung disease is not clear. Expression of integrins αVβ3 (ITGAVB3) or αVβ5 (ITGAVB5) on pulmonary T cells was observed by double-stain immunofluorescence confocal microscopy in six out of six patients with scleroderma lung disease, as well as in the animal models of pulmonary CCL18 overexpression that manifests in selective T lymphocytic infiltration of the lungs and T cell-dependent pulmonary fibrosis. Flow cytometry of bronchoalveolar lavage T cells confirmed expression of integrins on more than 10% (up to 50%) of pulmonary T cells in 14 of 25 scleroderma patients and in all CCL18-overexpressing mice; Q-PCR experiments confirmed elevated integrin mRNAs in purified BAL T cells. There was no expression of ITGAVB3 or ITGAVB5 on T cells from the lungs of healthy volunteers or control mice. Injections of anti-ITGB3 blocking antibody or genetic deficiency of ITGB3 protected mice from CC18-induced inflammation and fibrosis. Jurkat cells that were forced to overexpress ITGAVB3 or ITGAVB5 induced Smad2 phosphorylation and nuclear translocation, and increases in collagen and α-smooth muscle actin expression in co-cultures with primary lung fibroblasts. Blocking anti-TGF-β antibodies attenuated such regulation in cell co-cultures. Thus, expression of integrins on pulmonary T cells contributes to interstitial lung disease by promoting T cell infiltration, TGF-β activation, and fibrosis.