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

Simone L Park1,2, Mark M Painter3,4, Sasikanth Manne3,4

  • 1Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. simone.park@pennmedicine.upenn.edu.

Nature Immunology
|December 30, 2025
PubMed

Insights

Chronic antigen stimulation creates distinct tissue-resident exhausted CD8+ T (TR-TEX) cells, different from memory (TRM) cells. TR-TEX cells uniquely predict immune checkpoint blockade response in patients.

Area of Science:

  • Immunology
  • Cell Biology
  • Chronic Disease Pathogenesis

Background:

  • CD8+ T cells coexpressing residency and exhaustion markers are linked to chronic disease outcomes.
  • The precise relationship between these cells, conventional tissue-resident memory (TRM) cells, and exhausted CD8+ T (TEX) cells remains undefined.

Purpose of the Study:

  • To elucidate the distinct developmental pathways and functional roles of tissue-resident exhausted TEX (TR-TEX) cells versus TRM cells in chronic antigen exposure settings.
  • To investigate the transcriptional regulation and therapeutic potential of TR-TEX cells in immune checkpoint blockade therapy.

Main Methods:

  • Comparative analysis of T cell populations under chronic antigen stimulation versus antigen clearance.
  • Transcriptional profiling to identify cell-state-specific regulatory networks, including Tox dependency.
  • In vivo studies assessing T cell responses to PD-1 pathway inhibition.

Main Results:

  • Chronic antigen stimulation generates TR-TEX cells, which are transcriptionally distinct from TRM cells and require Tox for residency programming.
  • TRM cells can differentiate into TEX cells under chronic antigen exposure, but TEX cells do not revert to TRM cells after antigen withdrawal.
  • TR-TEX cell presence selectively correlates with patient response to immune checkpoint blockade, and these cells, not TRM cells, respond to PD-1 inhibition in vivo.

Conclusions:

  • TR-TEX and TRM cells represent developmentally divergent CD8+ T cell states sharing tissue residency but differing in function during chronic disease.
  • TR-TEX cells are key players in disease control and represent a potential biomarker and therapeutic target for immune checkpoint blockade.

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