Restricted TCR Diversity and Expansion of CD177 ⁺ CD8 ⁺ and TLR4 ⁺ CD4 ⁺ T Cell Subsets in Septic Shock‐Associated Immunosuppression: A Single‐Cell Multi‐Omics Study

ABSTRACT Sepsis‐induced immunosuppression contributes to poor outcomes in sepsis patients, yet the mechanisms underlying T cell dysfunction remain incompletely understood. We integrated single‐cell RNA sequencing (scRNA‐seq), paired single‐cell T cell receptor sequencing (scTCR‐seq), bulk RNA sequencing (RNA‐seq), and flow cytometry to characterize CD8 + and CD4 + T cells in septic shock‐associated immunosuppression. Patients showed reduced T cell receptor (TCR) clonotype diversity in CD4 + T cells but not CD8 + T cells, with restricted clonality correlating with disease severity and lymphopenia. Integrative analyses revealed the expansion of two disease‐associated subsets: (1) CD177 + CD8 + T cells, enriched for interleukin‐17 (IL‐17) signaling with hyperexpanded clonotypes, and (2) TLR4 + CD4 + T cells, enriched for phagocytosis‐ and lysosome‐related programs with restricted clonality. Both subsets expressed high levels of S100A8, S100A9, and S100A12, correlating positively with severity scores and systemic inflammation. These findings provided single‐cell resolution evidence that clonal restriction of CD4 + T cells is a hallmark of septic immunosuppression. Our study depicted a single‐cell atlas linking CD4 + clonal restriction and the expansion of pathogenic T cell subsets to outcome, highlighting TCR clonality as a biomarker of immune competence and CD177 + CD8 + and TLR4 + CD4 + T cells as candidate therapeutic targets in septic shock‐associated immunosuppression.