Distinct landscapes of T-cell immunity and TCR repertoire between sepsis and pre-septic high-risk states

Sepsis remains a leading cause of in-hospital mortality worldwide. In recognition of its substantial morbidity and mortality even with optimal treatment, the World Health Organization has declared sepsis a global health priority. The immunoregulatory mechanisms in sepsis are highly complex, and the immune status during the disease course is closely associated with both short- and long-term patient outcomes, making early recognition and intervention critical for survival. While single-cell RNA sequencing (scRNA-seq) has been widely applied to decipher innate immune responses in sepsis patients, in-depth characterization of T lymphocyte subsets remains relatively limited. Urosepsis is a common complication of urinary tract stones. Although clinical studies have identified several risk factors for urosepsis, the immunological alterations in high-risk individuals are poorly understood. Here, we employed single-cell transcriptomics to investigate T-cell immunological changes in high-risk urosepsis patients and septic patients, complemented by single-cell T cell receptor (TCR) sequencing (scTCR-seq) to profile the peripheral TCR repertoire in these two pathological states. Our analysis revealed that, compared to non-high-risk controls, septic patients exhibited features of T cell exhaustion across multiple subsets, whereas high-risk individuals showed signs of enhanced T cell-mediated adaptive immunity. Notably, we identified a distinct CD4⁺ T cell subset (C10_Tn_IFN) and, through protein-protein interaction analysis, uncovered key protein targets (IFIT3, RSAD2) potentially regulating its interferon signaling pathway. Furthermore, we observed significantly reduced TCR diversity accompanied by altered CDR3 sequence characteristics and VJ gene usage frequencies in several CD4⁺ and CD8⁺ T cell subsets from sepsis patients. These findings provide important insights into the relationship between T cell functionality and the severity of infectious inflammation.