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<p>The anatomical source of infection is a major determinant of sepsis outcomes; however, how distinct sites shape immunity remains unclear. Here we applied multi-omic profiling, integrating single-cell transcriptomics, single-cell T cell receptor and B cell receptor sequencing, CITE-seq, bulk RNA sequencing and plasma proteomics, to analyze peripheral blood mononuclear cells and plasma from 281 adult and pediatric individuals with sepsis and controls. We identified an NR4A2<sup>+</sup> central memory CD4<sup>+</sup> T cell subset enriched in abdominal, pulmonary and skin sepsis, with features of exhaustion; genetic perturbations showed <i>Nr4a2</i> loss improved survival, while overexpression worsened it. Proinflammatory CD8<sup>+</sup> T, natural killer and natural killer T subsets expressing <i>CCL4</i>, <i>CCL3</i> and tumor necrosis factor expanded in adult abdominal and pulmonary sepsis, while pediatric pulmonary sepsis featured proliferative CD14<sup>+</sup> monocytes, findings validated in external single-cell cohorts and confirmed in 164 independent individuals. Plasma proteomics revealed shared mediators including interleukin-6 and EN-RAGE across anatomical sites and ages. Together, our findings delineate anatomical-specific and age-specific immune programs in sepsis, highlighting candidate targets for precision immunotherapy.</p>

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Single-cell multi-omic landscape reveals anatomical-specific immune features in adult and pediatric sepsis

  • 期刊论文

  • 发表日期：

    2025年12月3日

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  • Qian Ye,
  • Xiaofei Lai,
  • Yuliang Liu,
  • Zhengtao Zhang,
  • Yueqiang Fu,
  • Jie Luo,
  • Chengjun Liu,
  • Jun Duan,
  • Hao Ding,
  • Yuhan Liu,
  • Zhi Ao,
  • Yang Tao,
  • Shanmu Ai,
  • Wei Huang,
  • Lei Jiang,
  • Yi Liu,
  • Fang Xu,
  • Ju Cao

摘要

The anatomical source of infection is a major determinant of sepsis outcomes; however, how distinct sites shape immunity remains unclear. Here we applied multi-omic profiling, integrating single-cell transcriptomics, single-cell T cell receptor and B cell receptor sequencing, CITE-seq, bulk RNA sequencing and plasma proteomics, to analyze peripheral blood mononuclear cells and plasma from 281 adult and pediatric individuals with sepsis and controls. We identified an NR4A2+ central memory CD4+ T cell subset enriched in abdominal, pulmonary and skin sepsis, with features of exhaustion; genetic perturbations showed Nr4a2 loss improved survival, while overexpression worsened it. Proinflammatory CD8+ T, natural killer and natural killer T subsets expressing CCL4, CCL3 and tumor necrosis factor expanded in adult abdominal and pulmonary sepsis, while pediatric pulmonary sepsis featured proliferative CD14+ monocytes, findings validated in external single-cell cohorts and confirmed in 164 independent individuals. Plasma proteomics revealed shared mediators including interleukin-6 and EN-RAGE across anatomical sites and ages. Together, our findings delineate anatomical-specific and age-specific immune programs in sepsis, highlighting candidate targets for precision immunotherapy.