De Duve Institute, Université Catholique de Louvain, Brussels, Belgium.
De Duve Institute, Université Catholique de Louvain, Brussels, Belgium.
Cell Rep. 2024 Jul 23;43(7):114401. doi: 10.1016/j.celrep.2024.114401. Epub 2024 Jun 27.
Human CD8 tumor-infiltrating lymphocytes (TILs) with impaired effector functions and PD-1 expression are categorized as exhausted. However, the exhaustion-like features reported in TILs might stem from their activation rather than the consequence of T cell exhaustion itself. Using CRISPR-Cas9 and lentiviral overexpression in CD8 T cells from non-cancerous donors, we show that the T cell receptor (TCR)-induced transcription factor interferon regulatory factor 4 (IRF4) promotes cell proliferation and PD-1 expression and hampers effector functions and expression of nuclear factor κB (NF-κB)-regulated genes. While CD8 TILs with impaired interferon γ (IFNγ) production exhibit activation markers IRF4 and CD137 and exhaustion markers thymocyte selection associated high mobility group box (TOX) and PD-1, activated T cells in patients with COVID-19 do not demonstrate elevated levels of TOX and PD-1. These results confirm that IRF4 TILs are exhausted rather than solely activated. Our study indicates, however, that PD-1 expression, low IFNγ production, and active cycling in TILs are all influenced by IRF4 upregulation after T cell activation.
人类 CD8 肿瘤浸润淋巴细胞 (TILs) 具有受损的效应功能和 PD-1 表达，被归类为衰竭。然而，TILs 中报告的衰竭样特征可能源于其激活，而不是 T 细胞衰竭本身的结果。使用非癌症供体的 CD8 T 细胞中的 CRISPR-Cas9 和慢病毒过表达，我们表明 T 细胞受体 (TCR) 诱导的转录因子干扰素调节因子 4 (IRF4) 促进细胞增殖和 PD-1 表达，并阻碍效应功能和核因子 κB (NF-κB) 调节基因的表达。虽然产生受损的干扰素 γ (IFNγ) 的 CD8 TILs 表现出激活标志物 IRF4 和 CD137 以及衰竭标志物胸腺细胞选择相关高迁移率族框 (TOX) 和 PD-1，但 COVID-19 患者中的活化 T 细胞并未表现出 TOX 和 PD-1 的水平升高。这些结果证实了 IRF4 TILs 是衰竭的，而不仅仅是激活的。然而，我们的研究表明，PD-1 表达、低 IFNγ 产生和 TIL 中的活跃循环都受到 TCR 激活后 IRF4 上调的影响。
