Deletion of mTORC1 Activity in CD4+ T Cells Is Associated with Lung Fibrosis and Increased γδ T Cells

Abstract

Pulmonary fibrosis is a devastating, incurable disease in which chronic inflammation and dysregulated, excessive wound healing lead to progressive fibrosis, lung dysfunction, and ultimately death. Prior studies have implicated the cytokine IL-17A and Th17 cells in promoting the development of fibrosis. We hypothesized that loss of Th17 cells via CD4-specific deletion of mTORC1 activity would abrogate the development of bleomycin-induced pulmonary fibrosis. However, in actuality loss of Th17 cells led to increased mortality and fibrosis in response to bleomycin. We found that in the absence of Th17 cells, there was continued production of IL-17A by γδ T cells. These IL-17A+ γδ T cells were associated with increased lung neutrophils and M2 macrophages, accelerated development of fibrosis, and increased mortality. These data elucidate the critical role of IL-17A+ γδ T cells in promoting chronic inflammation and fibrosis, and reveal a novel therapeutic target for treatment of pulmonary fibrosis.

The Roles of Immune Cells in the Pathogenesis of Fibrosis

“…The protective roles of Tregs were regulated by mTOR in the repair of acute kidney injury [ 104 ]. Moreover, deletion of mTORC1 activity in CD4 + T cells resulted in increased inflammation, accelerated fibrosis development and increased mortality, which was associated with IL-17 production derived from γδT cells [ 136 ].…”

Periodontitis aggravates COPD through the activation of γδ T cell and M2 macrophage

“…Jin et al ( 29 ) implicated that commensal-bacteria activated γδ T cells in lung tissue and promoted lung adenocarcinoma through IL 17 production. Data in Vigeland’s study elucidate the critical role of IL 17A + γδ T cells in promoting chronic inflammation and fibrosis of the lung tissue ( 39 ).…”

“…Generally, IL 4, IL10, and IL 13 are considered the more common markers for inducing M2 polarization; however, existing studies have shown that in the lung tissue, γδ T cells could regulate M2 polarization of macrophages by producing IL17 and that M2 polarization could be significantly inhibited if γδ T cells was deficient or IL17 was blocked. In lung tissue, IL 17 expressed by activated γδ T cells could induce macrophage proliferation and M2 polarization, thus further affect disease progression ( 30 , 38 , 39 ). This procedure had been demonstrated in both pulmonary inflammation and lung fibrosis ( 38 , 39 ) as well as in OSCC with periodontitis models ( 35 ).…”

“…In lung tissue, IL 17 expressed by activated γδ T cells could induce macrophage proliferation and M2 polarization, thus further affect disease progression ( 30 , 38 , 39 ). This procedure had been demonstrated in both pulmonary inflammation and lung fibrosis ( 38 , 39 ) as well as in OSCC with periodontitis models ( 35 ). Therefore, does such an immune regulatory mechanism also exist in the COPD disease model and can periodontitis further promote COPD progression by regulating this mechanism?…”

“…Through chemokines, cytokines, and cell surface receptors, γδ T cells and macrophages may undergo some inter-regulation ( 35 – 37 ). IL 17 and IFN γ produced by γδ T cells can play an inflammatory role; meanwhile, IL 17 can also promote the M2 polarization of lung macrophages ( 38 , 39 ).…”