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 (<i>IFIT3, RSAD2</i>) 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.