During chronic stimulation, CD8⁺ T cells acquire an exhausted phenotype characterized by expression of inhibitory receptors, down-modulation of effector function, and metabolic impairments. T cell exhaustion protects from excessive immunopathology but limits clearance of virus-infected or tumor cells. We transcriptionally profiled antigen-specific T cells from mice infected with lymphocytic choriomeningitis virus strains that cause acute or chronic disease. T cell exhaustion during chronic infection was driven by high amounts of T cell receptor (TCR)-induced transcription factors IRF4, BATF, and NFATc1. These regulators promoted expression of inhibitory receptors, including PD-1, and mediated impaired cellular metabolism. Furthermore, they repressed the expression of TCF1, a transcription factor required for memory T cell differentiation. Reducing IRF4 expression restored the functional and metabolic properties of antigen-specific T cells and promoted memory-like T cell development. These findings indicate that IRF4 functions as a central node in a TCR-responsive transcriptional circuit that establishes and sustains T cell exhaustion during chronic infection.

在慢性刺激过程中，CD8 ⁺T细胞会获得精疲力竭的表型，其特征在于抑制性受体的表达，效应子功能的下调和代谢障碍。T细胞衰竭可防止过度的免疫病理，但会限制病毒感染或肿瘤细胞的清除。我们从感染了可导致急性或慢性疾病的淋巴细胞性脉络膜脑膜炎病毒株感染的小鼠中转录特异的抗原特异性T细胞。慢性感染期间的T细胞衰竭是由大量T细胞受体（TCR）诱导的转录因子IRF4，BATF和NFATc1驱动的。这些调节剂促进包括PD-1在内的抑制性受体的表达，并介导受损的细胞代谢。此外，他们抑制了TCF1的表达，TCF1是记忆T细胞分化所需的转录因子。减少IRF4表达恢复了抗原特异性T细胞的功能和代谢特性，并促进了记忆样T细胞的发育。这些发现表明，IRF4在TCR反应性转录回路中起着中心节点的作用，该回路在慢性感染过程中建立并维持T细胞的衰竭。