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<p>The presence of CD8<sup>+</sup> T cells coexpressing residency and exhaustion molecules in chronic diseases often correlate with clinical outcomes; however, the relationship between these cells and conventional tissue-resident memory (T<sub>RM</sub>) cells or exhausted CD8<sup>+</sup> T (T<sub>EX</sub>) cells is unclear. Here we show that chronic antigen stimulation drives development of tissue-resident T<sub>EX</sub> (TR-T<sub>EX</sub>) cells that are distinct from T<sub>RM</sub> cells generated after antigen clearance. TR-T<sub>EX</sub> and T<sub>RM</sub> cells are regulated by different transcriptional networks with only TR-T<sub>EX</sub> cells being Tox-dependent for residency programming. While T<sub>EX</sub> cells (including TR-T<sub>EX</sub>) are unable to generate T<sub>RM</sub> cells after antigen withdrawal, T<sub>RM</sub> cells differentiate into T<sub>EX</sub> cells upon chronic antigen exposure. Cell-state-specific transcriptional signatures reveal a selective association of TR-T<sub>EX</sub> cells with patient responses to immune checkpoint blockade, and only TR-T<sub>EX</sub> but not T<sub>RM</sub> cells responded to PD-1 pathway inhibition in vivo. These data suggest that TR-T<sub>EX</sub> and T<sub>RM</sub> cells are developmentally divergent cell states that share a tissue-residency program but have distinct roles in disease control.</p>

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Tissue-resident exhausted and memory CD8+ T cells have distinct ontogeny, function and roles in disease

  • 期刊论文

  • 发表日期：

    2025年12月29日

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  • Simone L. Park,
  • Mark M. Painter,
  • Sasikanth Manne,
  • Victor Alcalde,
  • Maura McLaughlin,
  • Matthew A. Sullivan,
  • Divij Mathew,
  • Leonel Torres,
  • Yinghui J. Huang,
  • David B. Reeg,
  • Naomi R. Douek,
  • Trenton Campos,
  • Max Klapholz,
  • Maria A. Cardenas,
  • Victoria Fang,
  • Shin Foong Ngiow,
  • Wumesh KC,
  • Rishi R. Goel,
  • Amy E. Baxter,
  • Jennifer E. Wu,
  • Melody Tan,
  • Corbett T. Berry,
  • Christoph T. Ellebrecht,
  • Alexander C. Huang,
  • Emily Papazian,
  • Ying Liu,
  • Karthik Rajasekaran,
  • Robert M. Brody,
  • Erica R. Thaler,
  • Devraj Basu,
  • Ahmed Diab,
  • Josephine R. Giles,
  • E. John Wherry

摘要

The presence of CD8+ T cells coexpressing residency and exhaustion molecules in chronic diseases often correlate with clinical outcomes; however, the relationship between these cells and conventional tissue-resident memory (TRM) cells or exhausted CD8+ T (TEX) cells is unclear. Here we show that chronic antigen stimulation drives development of tissue-resident TEX (TR-TEX) cells that are distinct from TRM cells generated after antigen clearance. TR-TEX and TRM cells are regulated by different transcriptional networks with only TR-TEX cells being Tox-dependent for residency programming. While TEX cells (including TR-TEX) are unable to generate TRM cells after antigen withdrawal, TRM cells differentiate into TEX cells upon chronic antigen exposure. Cell-state-specific transcriptional signatures reveal a selective association of TR-TEX cells with patient responses to immune checkpoint blockade, and only TR-TEX but not TRM cells responded to PD-1 pathway inhibition in vivo. These data suggest that TR-TEX and TRM cells are developmentally divergent cell states that share a tissue-residency program but have distinct roles in disease control.