In mice dermally infected with OVA-expressing vaccinia virus and administered OT-I cells, PD-1+ cells constituted the majority of skin OT-I Trms both during infection and after clearance. Anti-PD-1 reduced initial skin Trm formation, but did not impact later antigen recall potential, and PD-1 expression conferred a proliferative benefit in the skin, but not the LNs. DEGs from PD-1+ skin Trm were unique to this tissue site, upregulated during early Trm formation, and did not overlap with those of other T cell states. Induction of TGFβ signaling in the infection and engraftment models reversed the inhibitory effects of anti-PD-1 on skin Trm formation.
Contributed by Morgan Janes
ABSTRACT: Tissue-resident memory T (TRM) cells provide infectious, cancer and vaccine-trained immunity across barrier sites. TRM cells are implicated in autoimmunity, successful response to immune checkpoint blockade in the tumor microenvironment and toxicities that occur after immune checkpoint blockade in peripheral tissues. Here, we identified that signaling through the immune checkpoint programmed death receptor 1 (PD-1) strongly impacts the early specification of CD8+ TRM cells in the skin. PD-1 is expressed broadly across mouse and human skin TRM cells, in the absence of persistent infection, and is retained on skin TRM cells in aged mice. PD-1 supports early TRM cell colonization, skin-specific programming and silencing of other differentiation programs and promotes TGFβ responsivity and skin engraftment. Thus, PD-1 signaling mediates skin TRM cell specification during immune initiation. These findings may inform therapeutic PD-1 agonist and antagonist use to modulate successful peripheral memory.
Author Info: (1) Department of Dermatology, Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA. (2) Department of Dermatology, Meyer Cancer Center, Weill Cornell Medicine, New York,
Author Info: (1) Department of Dermatology, Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA. (2) Department of Dermatology, Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA. (3) Department of Dermatology, Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA. (4) Department of Immunology and Immunotherapy, Icahn School of Medicine at Mt. Sinai, New York, NY, USA. (5) Department of Microbiology and Immunology, Yonsei University College of Medicine, Seoul, South Korea. (6) Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. (7) Institute for Computational Biomedicine, Caryl and Israel Englander Institute for Precision Medicine, Weill Cornell Medicine, New York, NY, USA. (8) Department of Dermatology, Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA. (9) Department of Dermatology, Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA. (10) Department of Microbiology and Immunology, The University of Melbourne at The Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia. (11) Department of Microbiology and Immunology, The University of Melbourne at The Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia. School of Mathematics and Statistics, The University of Melbourne, Melbourne, Victoria, Australia. Walter and Eliza Hall Institute for Medical Research, Parkville, Victoria, Australia. (12) Department of Microbiology and Immunology, Yonsei University College of Medicine, Seoul, South Korea. (13) Department of Immunology, Mayo Clinic, Scottsdale, AZ, USA. (14) Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. (15) Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. (16) Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. (17) Department of Dermatology, Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA. (18) Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. (19) Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. (20) Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. (21) Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. (22) Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Dana-Farber/Brigham and Women's Cancer Center, Boston, MA, USA. (23) Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Dana-Farber/Brigham and Women's Cancer Center, Boston, MA, USA. (24) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. (25) Department of Microbiology and Immunology, The University of Melbourne at The Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia. (26) Department of Immunology and Immunotherapy, Icahn School of Medicine at Mt. Sinai, New York, NY, USA. Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (27) Fred Hutchinson Cancer Research Center, Vaccine and Infectious Disease Division, Seattle, WA, USA. (28) Institute for Computational Biomedicine, Caryl and Israel Englander Institute for Precision Medicine, Weill Cornell Medicine, New York, NY, USA. (29) Department of Genetics and Genomic Science, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Population Health Science and Policy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (30) Department of Dermatology, Englander Institute for Precision Medicine at Weill Cornell Medicine, New York, NY, USA. niroananda@gmail.com. Parker Institute for Cancer Immunotherapy and Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA. niroananda@gmail.com. Department of Microbiology and Immunology, Englander Institute for Precision Medicine at Weill Cornell Medicine, New York, NY, USA. niroananda@gmail.com. Immunology and Microbial Pathogenesis Program, Weill Cornell Medical College, New York, NY, USA. niroananda@gmail.com.
