Role of Immune Checkpoint Proteins in Idiopathic Pulmonary Fibrosis

Abstract Idiopathic pulmonary fibrosis (IPF) is a fibrotic lung disease, with unknown etiopathogenesis and suboptimal therapeutic options. Due to the lack of clinical efficacy of standard immuno-suppressants in IPF, the role of the immune response in this disease remains elusive. Nevertheless, previous reports have shown that increased T cell numbers and phenotype is predictive of prognosis in IPF, suggesting that these cells might have a role in this disease. Transcriptomic analysis of CD3+ T cells isolated from IPF lungs removed prior to lung transplant (i.e. explant lung) revealed a loss of CD28 expression and both elevated checkpoint and lymphocyte activation pathways. Flow cytometric analysis of a mixture of immune and non-immune cells isolated from explanted IPF lungs showed elevated PD-1 and CTLA4 protein expression on CD4- lymphocytes and PD-L1 expression on EpCAM+ and CD45- EpCAM- cells. Lung remodeling and loss of BAL surfactant protein C were observed in NOD SCID IL-2Rγ-/- (NSG) mice that received an intravenous injection of a mixture of IPF cells, including purified IPF T cells. Finally, in humanized NSG mice, anti-CTLA4, but not anti-PD1, mAb treatment induced an expansion of CD3+ T cells and accelerated lung fibrosis. Together, these results demonstrate that IPF T cells are profibrotic but the immune checkpoint protein, CTLA-4, appears to limit this effect in IPF.