Regulatory Role of γδ T Cells in the Recruitment of CD4+ and CD8+ T Cells to Lung and Subsequent Pulmonary Fibrosis

Abstract

The mechanisms by which T cells accumulate in the lungs of patients with pulmonary fibrosis are poorly understood. Because the lung is continually exposed to microbial agents from the environment, we repeatedly exposed C57BL/6 mice to the ubiquitous microorganism, Bacillus subtilis, to determine whether chronic exposure to an inhaled microorganism could lead to T cell accumulation in the lungs and subsequent pulmonary fibrosis. C57BL/6 mice repeatedly treated with B. subtilis for 4 consecutive weeks developed a 33-fold increase in the number of CD4+ T cells and a 354-fold increase in γδ T cells in the lung. The γδ T cells consisted almost entirely of Vγ6/Vδ1+ cells, a murine subset bearing an invariant TCR the function of which is still unknown. Treatment of C57BL/6 mice with heat-killed vs live B. subtilis resulted in a 2-fold increase in the number of CD4+ T cells in the lung but no expansion of γδ T cells indicating that γδ cells accumulate in response to live microorganisms. In addition, mice treated with heat-killed B. subtilis developed significantly increased pulmonary fibrosis compared with mice treated with the live microorganism. Mice deficient in Vγ6/Vδ1+ T cells when treated with B. subtilis had a 231-fold increase in lung CD4+ T cells and significantly increased collagen deposition compared with wild-type C57BL/6 mice, consistent with an immunoregulatory role for the Vγ6/Vδ1 T cell subset. These findings indicate that chronic inhalation of B. subtilis can result in T cell accumulation in the lung and fibrosis, constituting a new model of immune-mediated pulmonary fibrosis.

γδ T Cells Attenuate Bleomycin-Induced Fibrosis through the Production of CXCL10

“…24,41 This is in contrast to the ␥␦ KO response to bleomycin, in which there is a decrease in inflammatory cells in the BAL fluid. However, histological features demonstrate pronounced hypercellularity and intimal thickening in lung parenchyma.…”

“…39 This makes them interesting targets to study in the progression of a disease, such as IPF, because it occurs in response to epithelial injury. In a chronic B. subtilis infection, mice lacking ␥␦ T cells demonstrated an enhanced fibrotic phenotype 24 because of enhanced inflammation. In support of our study, Braun et al 36 recently showed that mice lacking ␥␦ T cells had slower epithelial repair in response to bleomycin treatment.…”

“…At higher concentrations and more long-term models, such as hypersensitivity pneumonitis, 24,41 IL-17 may lead to a more protracted inflammatory state. In shorter-term "single-hit" models, such as bleomycin and silica, 48 in which IL-17 production is limited, IL-17 may have a less inflammatory role.…”

“…23 For chronic Bacillus subtilis infection, mice lacking ␥␦ T cells demonstrated an enhanced fibrotic phenotype. 24 Because of the potential role of these cells in epithelial repair (a process that has been hypothesized to be critical for the prevention of fibrosis), we hypothesized that ␥␦ T cells are critical for resolving fibrogenic insults in the lung.…”

CCR6 and NK1.1 distinguish between IL‐17A and IFN‐γ‐producing γδ effector T cells

“…The production of innate IL-17A by gd T cells appears to be essential in situations where an effective defence against extra-cellular bacteria or fungi relies on the fast mobilization of neutrophils [4,[6][7][8][9]. Moreover, IL-17A-producing gd T cells have been described to play important roles in immunopathologic diseases such as collageninduced arthritis [10], experimental pulmonary fibrosis [11], and in experimental autoimmune encephalitis [12,13].In contrast to CD4 1 Th cells that can develop into Th17 cells after encounter of specific cognate TCR Ag [14][15][16], it is not clear which stimuli induce IL-17A production by gd T cells in vivo. This essentially results from a lack of information about physiological gd TCR ligands.…”