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

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

doi:10.1038/s41590-025-02352-y

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. Epub 2025 Dec 29.

Authors

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}, Alexander C Huang^{4

12}, Emily Papazian¹³, Ying Liu¹³, Karthik Rajasekaran¹³, Robert M Brody¹³, Erica R Thaler¹³, Devraj Basu¹³, 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. simone.park@pennmedicine.upenn.edu.
² Institute for Immunology and Immune Health, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. simone.park@pennmedicine.upenn.edu.
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. wherry@pennmedicine.upenn.edu.
¹⁵ Institute for Immunology and Immune Health, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. wherry@pennmedicine.upenn.edu.
¹⁶ Parker Institute for Cancer Immunotherapy at University of Pennsylvania, Philadelphia, PA, USA. wherry@pennmedicine.upenn.edu.

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

MeSH terms

Animals
CD8-Positive T-Lymphocytes* / immunology
Cell Differentiation / immunology
Humans
Immune Checkpoint Inhibitors / pharmacology
Immunologic Memory* / immunology
Memory T Cells* / immunology
Mice
Mice, Inbred C57BL
Mice, Transgenic
Programmed Cell Death 1 Receptor / antagonists & inhibitors

Substances

Programmed Cell Death 1 Receptor
Immune Checkpoint Inhibitors

Abstract

MeSH terms

Substances

Grants and funding