2. Academic Validation
  3. Tissue-resident exhausted and memory CD8+ T cells have distinct ontogeny, function and role in disease

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

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.

Figures
Products