Tissue-resident exhausted and memory CD8+ T cells have distinct ontogeny, function and role in disease
(1) Park SL (2) Painter MM (3) Manne S (4) Alcalde V (5) McLaughlin M (6) Sullivan MA (7) Mathew D (8) Torres L (9) Huang YJ (10) Reeg DB (11) Douek NR (12) Campos T (13) Klapholz M (14) Cardenas MA (15) Fang V (16) Ngiow SF (17) Kc W (18) Goel RR (19) Baxter AE (20) Wu JE (21) Tan M (22) Berry CT (23) Ellebrecht CT (24) Alexander HC (25) Papazian E (26) Liu Y (27) Rajasekaran K (28) Brody RM (29) Thaler ER (30) Basu D (31) Diab A (32) Giles JR (33) Wherry EJ
Park et al. showed that chronic antigen exposure drove a distinct lineage of tissue-resident exhausted CD8+ T cells (TR-TEX) that was developmentally and functionally separate from tissue-resident memory (TRM) cells formed after antigen clearance. TR-TEX (Tox-dependent) and TRM (Tox-independent) cells shared residency features, but were governed by divergent transcriptional and epigenetic programs. TRM cells retained plasticity to differentiate into TEX cells under chronic stimulation, while committed TEX cells failed to generate TRM cells after antigen withdrawal. TR-TEX cells responded to PD-1 pathway blockade in vivo, and were associated with patient responses to ICB.
Contributed by Shishir Pant
(1) Park SL (2) Painter MM (3) Manne S (4) Alcalde V (5) McLaughlin M (6) Sullivan MA (7) Mathew D (8) Torres L (9) Huang YJ (10) Reeg DB (11) Douek NR (12) Campos T (13) Klapholz M (14) Cardenas MA (15) Fang V (16) Ngiow SF (17) Kc W (18) Goel RR (19) Baxter AE (20) Wu JE (21) Tan M (22) Berry CT (23) Ellebrecht CT (24) Alexander HC (25) Papazian E (26) Liu Y (27) Rajasekaran K (28) Brody RM (29) Thaler ER (30) Basu D (31) Diab A (32) Giles JR (33) Wherry EJ
Park et al. showed that chronic antigen exposure drove a distinct lineage of tissue-resident exhausted CD8+ T cells (TR-TEX) that was developmentally and functionally separate from tissue-resident memory (TRM) cells formed after antigen clearance. TR-TEX (Tox-dependent) and TRM (Tox-independent) cells shared residency features, but were governed by divergent transcriptional and epigenetic programs. TRM cells retained plasticity to differentiate into TEX cells under chronic stimulation, while committed TEX cells failed to generate TRM cells after antigen withdrawal. TR-TEX cells responded to PD-1 pathway blockade in vivo, and were associated with patient responses to ICB.
Contributed by Shishir Pant
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.
Author Info:
(1) Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. simone.park@pennmedicine.upen
n.edu. Institute for Immunology and Immune Health, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. simone.park@pennmedicine.upenn.edu. (2) Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. Institute for Immunology and Immune Health, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. (3) Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. Institute for Immunology and Immune Health, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. (4) Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. Institute for Immunology and Immune Health, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. (5) Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. Institute for Immunology and Immune Health, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. (6) Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. Institute for Immunology and Immune Health, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. Graduate Group in Biochemistry and Molecular Biophysics, University of Pennsylvania, Philadelphia, PA, USA. (7) Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. Institute for Immunology and Immune Health, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. Parker Institute for Cancer Immunotherapy at University of Pennsylvania, Philadelphia, PA, USA. (8) Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. Institute for Immunology and Immune Health, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. (9) Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. Institute for Immunology and Immune Health, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. Parker Institute for Cancer Immunotherapy at University of Pennsylvania, Philadelphia, PA, USA. (10) Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. Institute for Immunology and Immune Health, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. Department of Medicine II (Gastroenterology, Hepatology, Endocrinology and Infectious Diseases), Freiburg University Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany. (11) Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. Institute for Immunology and Immune Health, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. (12) Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. Institute for Immunology and Immune Health, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. (13) Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. Institute for Immunology and Immune Health, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. Parker Institute for Cancer Immunotherapy at University of Pennsylvania, Philadelphia, PA, USA. (14) Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. Institute for Immunology and Immune Health, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. (15) Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. Institute for Immunology and Immune Health, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. Department of Dermatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. (16) Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. Institute for Immunology and Immune Health, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. Parker Institute for Cancer Immunotherapy at University of Pennsylvania, Philadelphia, PA, USA. (17) Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. Institute for Immunology and Immune Health, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. Division of Cardiovascular Medicine, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, USA. (18) Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. Institute for Immunology and Immune Health, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. Department of Medicine, Massachusetts General Hospital, Boston, MA, USA. (19) Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. Institute for Immunology and Immune Health, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. (20) Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. Institute for Immunology and Immune Health, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. Parker Institute for Cancer Immunotherapy at University of Pennsylvania, Philadelphia, PA, USA. (21) Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. Institute for Immunology and Immune Health, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. (22) Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. Department of Dermatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. (23) Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. Department of Dermatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. (24) Institute for Immunology and Immune Health, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. Department of Medicine: Hematology and Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. (25) Department of Otorhinolaryngology: Head and Neck Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. (26) Department of Otorhinolaryngology: Head and Neck Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. (27) Department of Otorhinolaryngology: Head and Neck Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. (28) Department of Otorhinolaryngology: Head and Neck Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. (29) Department of Otorhinolaryngology: Head and Neck Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. (30) Department of Otorhinolaryngology: Head and Neck Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. (31) Institute for Immunology and Immune Health, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. Department of Otorhinolaryngology: Head and Neck Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. (32) Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. Institute for Immunology and Immune Health, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. Parker Institute for Cancer Immunotherapy at University of Pennsylvania, Philadelphia, PA, USA. (33) Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. wherry@pennmedicine.upenn.edu. Institute for Immunology and Immune Health, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. wherry@pennmedicine.upenn.edu. Parker Institute for Cancer Immunotherapy at University of Pennsylvania, Philadelphia, PA, USA. wherry@pennmedicine.upenn.edu.
Citation: Nat Immunol 2026 Jan 27:110-125 Epub12/29/2025
