效应功能和 PD-1 表达受损的人 CD8 肿瘤浸润淋巴细胞 (TIL) 被归类为耗尽型。然而，TIL 中报道的类似耗竭的特征可能源于它们的激活，而不是 T 细胞耗竭本身的结果。使用 CRISPR-Cas9 和慢病毒在非癌性供体 CD8 T 细胞中过表达，我们发现 T 细胞受体 (TCR) 诱导的转录因子干扰素调节因子 4 (IRF4) 可促进细胞增殖和 PD-1 表达并阻碍效应子功能以及核因子κB (NF-κB) 调节基因的表达。虽然干扰素 γ (IFNγ) 产生受损的 CD8 TIL 表现出激活标记物 IRF4 和 CD137 以及与高迁移率族盒 (TOX) 和 PD-1 相关的胸腺细胞选择耗竭标记物，但 COVID-19 患者中的激活 T 细胞并未表现出升高的水平TOX 和 PD-1。这些结果证实 IRF4 TIL 被耗尽而不是被单独激活。然而，我们的研究表明，TIL 中的 PD-1 表达、低 IFNγ 产生和活跃循环均受到 T 细胞激活后 IRF4 上调的影响。版权所有 © 2024 作者。由爱思唯尔公司出版。保留所有权利。

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.Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.