CD8+ T细胞耗竭（TEX）影响T细胞清除慢性感染或癌症的能力。虽然TEX具有低功能性，但一些TEX保留了效应基因签名，这是与杀手凝集素样受体（KLR）表达相关的特征。尽管KLR+ TEX（TKLR）可能改善慢性抗原的控制，但调节此人群的信号分子尚不清楚。通过使用单细胞RNA测序（scRNA-seq）、流式细胞术、RNA速度和单细胞T细胞受体测序（scTCR-seq），我们证明了删除伪激酶Trib1使TEX朝向具有丰富TKLR的CX3CR1+中间体转变，并通过克隆T细胞扩张。移植研究表明，Trib1缺陷细胞中CD8+ TKLR的转变是CD8内源性的，而CD4去除研究表明，CD4+ T细胞对Trib1有条件敲除小鼠中改善病毒控制是必需的。此外，Trib1的损失增强了抗程序性死亡配体1（PD-L1）阻断以改善病毒清除。这些数据确定了Trib1作为调节CD8+ TEX的重要调节因子，其靶向能够增强TKLR效应状态并改善检查点抑制剂疗法。版权所有©2023年作者。由Elsevier Inc.出版。版权所有。

CD8+ T cell exhaustion (TEX) impairs the ability of T cells to clear chronic infection or cancer. While TEX are hypofunctional, some TEX retain effector gene signatures, a feature associated with killer lectin-like receptor (KLR) expression. Although KLR+ TEX (TKLR) may improve control of chronic antigen, the signaling molecules regulating this population are poorly understood. Using single-cell RNA sequencing (scRNA-seq), flow cytometry, RNA velocity, and single-cell T cell receptor sequencing (scTCR-seq), we demonstrate that deleting the pseudokinase Trib1 shifts TEX toward CX3CR1+ intermediates with robust enrichment of TKLR via clonal T cell expansion. Adoptive transfer studies demonstrate this shift toward CD8+ TKLR in Trib1-deficient cells is CD8 intrinsic, while CD4-depletion studies demonstrate CD4+ T cells are required for improved viral control in Trib1 conditional knockout mice. Further, Trib1 loss augments anti-programmed death-ligand 1 (PD-L1) blockade to improve viral clearance. These data identify Trib1 as an important regulator of CD8+ TEX whose targeting enhances the TKLR effector state and improves checkpoint inhibitor therapy.Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.