Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease causing irreversible lung scarring and loss of pulmonary function. IPF Patients suffer from a high rate of pulmonary infections and acute exacerbations of disease that further contribute to pulmonary decline. Low expression of the inducible T-cell costimulatory molecule (ICOS) in peripheral blood mononuclear cells predicts decreased survival of IPF patients, but the mechanisms by which ICOS protects are unclear. Using a model of bleomycin-induced lung injury and fibrosis, we now demonstrate that ICOS expression enhances survival from lung injury rather than regulating fibrogenesis. Of ICOS expressing cells, type 2 innate lymphocytes (ILC2s) are the first to respond to bleomycin-induced injury, and this expansion is ICOS-dependent. Interestingly, a similar decrease in ICOS+ ILCs was found in lung tissue from IPF patients. IL-5, produced primarily by ILC2s, was significantly reduced after lung injury in ICOS−/− mice, and strikingly, treatment with IL-5 protected both ICOS−/− and wild type mice from mortality. These results imply that low ICOS expression and decreased lung ILC2s in IPF patients may contribute to poor recovery from infections and acute exacerbation, and that IL-5 treatment may be a novel therapeutic strategy to overcome these defects and protect against lung injury.

Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease causing irreversible lung scarring and loss of pulmonary function. RNA analysis has shown that patients with IPF have reduced ICOS expression in peripheral blood mononuclear cells. We now show that ICOS surface expression on CD4 T cells positively correlates with lung function in patients with IPF. However, whether decreased ICOS is a result of disease progression or playing a role in the pathogenesis is unclear. Therefore, using bleomycin to induce pulmonary fibrosis in mice, we found that ICOS was decreased in peripheral CD4 T cells similar to our findings in patients. In contrast, ICOS was increased on lung CD4 T cells by 3d post-bleomycin and remained elevated through 21d at the height of collagen deposition. Compared to wild-type B6 mice, ICOS-deficient mice had increased weight loss and mortality after bleomycin challenge, suggesting a protective role for ICOS. Strikingly, ILC2s expanded in the lung at 3d post-bleomycin in B6 mice, but not in ICOS-deficient mice. In B6 mice, ILC2 expansion was associated with CD4 T cell infiltration at 5d and Th2 cytokine production in the draining lymph nodes at 21d. However, ICOS-deficient mice that survived the initial bleomycin insult failed to recruit T cells to the lungs and had less IL-13 in the draining lymph nodes. Overall, these results indicate that ICOS expression promotes lung tissue repair by promoting both innate and adaptive type-2 immune responses.

The role of the adaptive immune response in idiopathic pulmonary fibrosis (IPF) has been an area of debate. Several studies have shown that patients with IPF had increased numbers of T cells in their lungs, suggesting that these cells may play a role in disease pathogenesis. We have found that decreased expression of an important co-inhibitory molecule, B- and T- lymphocyte attenuator (BTLA) on peripheral blood CD4+ T cells is correlated with IPF patients most likely to rapidly progress in their disease course. Based on these findings, the objective of our study was to determine the role of BTLA on CD4+ T cells in the development of pulmonary fibrosis by utilizing a mouse model of bleomycin-induced pulmonary fibrosis. We found that, similar to our patient studies, bleomycin treated WT mice express decreased levels of BTLA on CD4+ T cells compared to untreated WT mice. BTLA-/- mice exhibited significantly increased weight loss and pulmonary fibrosis compared to WT mice. However, CD4+ depletion in the BTLA-/- mice prior to bleomycin challenge protected these mice, as they lost less weight had decreased lung collagen deposition. These findings support a significant role for the loss of BTLA on CD4+ T cells in the pathogenesis of fibrotic disease progression.