ICOS deficiency results in defective ILC2 expansion, impaired Th2 responses, and increased mortality after bleomycin-induced lung injury (HUM1P.264)

Abstract

Abstract 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.