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.

中文翻译：

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特发性肺纤维化中 CD28null T 细胞的特征。

特发性肺纤维化 (IPF) 是一种纤维化肺病，其发病机制未知且治疗选择不理想。以前的报告表明，增加的 T 细胞数量和 CD28^无效表型可预测 IPF 的预后，表明这些细胞可能在这种疾病中起作用。外植肺细胞悬浮液的流式细胞术分析显示，相对于正常肺外植体，IPF中 CD8 ⁺ CD28^{无效T 细胞显着增加。从 IPF 肺外植体分离的 CD3 +} T 细胞的转录组学分析显示，相对于正常 T 细胞，IPF 中 CD28 转录物表达缺失和促炎细胞因子表达升高。IPF 肺外植体来源的 T 细胞（富含 CD28^null T 细胞），但正常供体肺 CD28 ⁺ T 细胞不会在人源化 NSG 小鼠中诱导地塞米松抗性肺重塑。最后，CD28 ^{null T 细胞表达相似的 CTLA4 和相对于 CD28 +} T 细胞显着更高水平的 PD-1 蛋白，并且在人源化 NSG 小鼠中阻断任何一种蛋白，使用抗 CTLA4 或抗 PD1，mAb 治疗加速肺纤维化. 总之，这些结果表明 IPF CD28^无效T 细胞可能促进肺纤维化，但免疫检查点蛋白 CTLA-4 和 PD-1 似乎限制了这种作用。