TOX Does Not Drive Sepsis‐Induced T‐Cell Exhaustion

Abstract

The immune system undergoes profound dysregulation in sepsis, characterized by hyperinflammation in the acute phase followed by long‐lasting immunosuppression. T‐cell exhaustion has been proposed as one facet of sepsis‐related immunosuppression, which is characterized by impaired effector function and continuous expression of PD1. However, the current analysis of T‐cell exhaustion in the post‐sepsis is inadequate. Our current study has identified a progressive increase in the frequency of CD44+CD11a+ memory T cells during the post‐sepsis phase, accompanied by the upregulation of exhaustion markers (PD‐1, Lag3, and Tim3) and functional impairments in these cells. TOX is traditionally recognized as a key regulator driving CD8+ T‐cell exhaustion in cancer and chronic infection. However, we demonstrate that TOX does not play a critical role in T‐cell exhaustion during chronic sepsis but rather is involved in T‐cell effector function. Both knockout and “knockdown” of TOX failed to alleviate sepsis‐induced T‐cell exhaustion. Instead, deletion of TOX impaired the effector function of T cells in chronic sepsis, contradicting its impact on short‐term TCR engagement. Our study provides a novel insight into sepsis‐induced T‐cell exhaustion, highlighting the distinct characteristics of T‐cell exhaustion programmed by sepsis.