Characterization of CD28(null) T cells in Idiopathic Pulmonary Fibrosis

Idiopathic pulmonary fibrosis (IPF) is a fibrotic lung disease, with unknown etiopathogenesis and suboptimal therapeutic options. Previous reports have shown that increased T cell numbers and CD28(null) phenotype is predictive of prognosis in IPF, suggesting that these cells might have a role in this disease. Flow cytometric analysis of explanted lung cellular suspensions showed a significant increase in CD8(+) CD28(null) T cells in IPF relative to normal lung explants. Transcriptomic analysis of CD3(+) T cells isolated from IPF lungs explants revealed a loss of CD28 transcript expression and elevation of proinflammatory cytokine expression in IPF relative to normal T cells. IPF lung explant derived T cells (enriched with CD28(null) T cells), but not normal donor lung CD28(+) T cells induced dexamethasone resistant lung remodeling in humanized NSG mice. Finally, CD28(null) T cells expressed similar CTLA4 and significantly higher levels of PD-1 proteins relative to CD28(+) T cells and blockade of either proteins in humanized NSG mice, using anti-CTLA4, or anti-PD1, mAb treatment accelerated lung fibrosis. Together, these results demonstrate that IPF CD28(null) T cells may promote lung fibrosis but the immune checkpoint proteins, CTLA-4 and PD-1, appears to limit this effect.