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

  • Nat Immunol. 2026 Jan;27(1):110-125. doi: 10.1038/s41590-025-02352-y.
Simone L Park  1  2 ,  Mark M Painter  3  4 ,  Sasikanth Manne  3  4 ,  Victor Alcalde  3  4 ,  Maura McLaughlin  3  4 ,  Matthew A Sullivan  3  4  5 ,  Divij Mathew  3  4  6 ,  Leonel Torres  3  4  7 ,  Yinghui J Huang  3  4  6 ,  David B Reeg  3  4  8 ,  Naomi R Douek  3  4 ,  Trenton Campos  3  4 ,  Max Klapholz  3  4  6 ,  Maria A Cardenas  3  4 ,  Victoria Fang  3  4  9 ,  Shin Foong Ngiow  3  4  6 ,  Wumesh Kc  3  4  10 ,  Rishi R Goel  3  4  11 ,  Amy E Baxter  3  4 ,  Jennifer E Wu  3  4  6 ,  Melody Tan  3  4  7 ,  Corbett T Berry  7  9 ,  Christoph T Ellebrecht  7  9 ,  Huang C Alexander  4  12 ,  Emily Papazian  13 ,  Ying Liu  13 ,  Karthik Rajasekaran  13 ,  Robert M Brody  13 ,  Erica R Thaler  13 ,  Devraj Basu  13 ,  Ahmed Diab  4  13 ,  Josephine R Giles  3  4  6 ,  E John Wherry  14  15  16
Affiliations
  • 1. Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. [email protected].
  • 2. Institute for Immunology and Immune Health, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. [email protected].
  • 3. Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • 4. Institute for Immunology and Immune Health, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • 5. Graduate Group in Biochemistry and Molecular Biophysics, University of Pennsylvania, Philadelphia, PA, USA.
  • 6. Parker Institute for Cancer Immunotherapy at University of Pennsylvania, Philadelphia, PA, USA.
  • 7. Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • 8. Department of Medicine II (Gastroenterology, Hepatology, Endocrinology and Infectious Diseases), Freiburg University Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
  • 9. Department of Dermatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • 10. Division of Cardiovascular Medicine, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, USA.
  • 11. Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.
  • 12. Department of Medicine: Hematology and Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • 13. Department of Otorhinolaryngology: Head and Neck Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • 14. Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. [email protected].
  • 15. Institute for Immunology and Immune Health, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. [email protected].
  • 16. Parker Institute for Cancer Immunotherapy at University of Pennsylvania, Philadelphia, PA, USA. [email protected].
PMID: 41461986 DOI: 10.1038/s41590-025-02352-y
Abstract

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.

Products