TOX Does Not Drive Sepsis-Induced T-Cell Exhaustion

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.