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 lung explants revealed a loss of CD28-transcript expression and elevation of pro-inflammatory 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.