{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,29]],"date-time":"2026-07-29T01:53:09Z","timestamp":1785289989648,"version":"3.55.0"},"reference-count":65,"publisher":"National Academy of Sciences","issue":"15","license":[{"start":{"date-parts":[[2026,4,8]],"date-time":"2026-04-08T00:00:00Z","timestamp":1775606400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000060","name":"HHS | NIH | National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["P01AI056299"],"award-info":[{"award-number":["P01AI056299"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000054","name":"HHS | NIH | National Cancer Institute","doi-asserted-by":"publisher","award":["P01CA236749"],"award-info":[{"award-number":["P01CA236749"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000054","name":"HHS | NIH | National Cancer Institute","doi-asserted-by":"publisher","award":["P50CA217691"],"award-info":[{"award-number":["P50CA217691"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000054","name":"HHS | NIH | National Cancer Institute","doi-asserted-by":"publisher","award":["DRP of P50CA217691"],"award-info":[{"award-number":["DRP of P50CA217691"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000060","name":"HHS | NIH | National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["R01AI030048"],"award-info":[{"award-number":["R01AI030048"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2026,4,14]]},"abstract":"<jats:p>Anti-programmed cell death 1 (PD-1) antibody therapy is now widely used in various cancers. However, the role of the antibody Fc region in PD-1 directed immunotherapy is not well understood. Preclinical studies commonly use species-mismatched rat anti-mouse antibodies, which may not accurately reflect antibody-Fc gamma receptor (Fc\u03b3R) interactions. Here, we used mouse anti-mouse PD-1 antibodies to investigate how the Fc region influences therapeutic efficacy for enhancing CD8 T cell responses using mouse models of chronic lymphocytic choriomeningitis virus infection and CT26 tumors. Treatment with these mouse anti-mouse PD-1 antibodies caused preferential depletion of PD-1+ virus-specific CD8 T cells in the liver, resulting in increased viral titers. These effects of mouse anti-PD-1 antibodies were Fc dependent since mutating the Fc region to block Fc\u03b3R interaction prevented PD-1+ CD8 T cell depletion and resulted in effective immunotherapy. Using mice lacking activating Fc\u03b3R III or inhibitory Fc\u03b3R IIb, we found that depletion of PD-1+ CD8 T cells was mediated via activating Fc\u03b3R III. Furthermore, we determined that phagocytic cells, not natural killer cells, were the in vivo effectors that mediated depletion of PD-1+ CD8 T cells. Similar depletion of tumor-specific CD8 T cells and reduced tumor control were observed in the CT26 model with Fc-intact mouse anti-mouse PD-1 treatment. These findings highlight potential negative effects of Fc-functional anti-PD-1 antibodies in therapies for liver cancer, liver metastases, and chronic hepatotropic viral infections. Conversely, Fc\u03b3R-mediated depletion could benefit \u201cagonistic\u201d anti-PD-1 antibodies for treatment of autoimmunity. Our research emphasizes the importance of Fc region in tailoring PD-1 therapies for diverse clinical applications.<\/jats:p>","DOI":"10.1073\/pnas.2427192123","type":"journal-article","created":{"date-parts":[[2026,4,8]],"date-time":"2026-04-08T17:04:44Z","timestamp":1775667884000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":1,"title":["Selective depletion of virus-specific CD8 T cells from the liver after PD-1 therapy with Fc-intact antibody during chronic infection"],"prefix":"10.1073","volume":"123","author":[{"given":"Masao","family":"Hashimoto","sequence":"first","affiliation":[{"name":"Emory Vaccine Center, Emory University School of Medicine","place":["Atlanta"]},{"name":"Department of Microbiology and Immunology, Emory University School of Medicine","place":["Atlanta"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5650-1563","authenticated-orcid":false,"given":"Tahseen H.","family":"Nasti","sequence":"additional","affiliation":[{"name":"Emory Vaccine Center, Emory University School of Medicine","place":["Atlanta"]},{"name":"Department of Microbiology and Immunology, Emory University School of Medicine","place":["Atlanta"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hyun-Tak","family":"Jin","sequence":"additional","affiliation":[{"name":"Emory Vaccine Center, Emory University School of Medicine","place":["Atlanta"]},{"name":"Department of Microbiology and Immunology, Emory University School of Medicine","place":["Atlanta"]},{"name":"CHA Biotech, CHA Bio Complex","place":["Seongnam-si, Gyeonggi-do, Republic of Korea"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melissa","family":"Bu","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Dana-Farber Cancer Institute","place":["Boston"]},{"name":"Department of Medicine, Harvard Medical School","place":["Boston"]},{"name":"Medical Scientist Training Program, UCSF Graduate Division, School of Medicine, University of California","place":["San Francisco"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Koichi","family":"Araki","sequence":"additional","affiliation":[{"name":"Emory Vaccine Center, Emory University School of Medicine","place":["Atlanta"]},{"name":"Department of Microbiology and Immunology, Emory University School of Medicine","place":["Atlanta"]},{"name":"Division of Infectious Diseases, Center for Inflammation and Tolerance, Cincinnati Children\u2019s Hospital Medical Center","place":["Cincinnati"]},{"name":"Department of Pediatrics, University of Cincinnati College of Medicine","place":["Cincinnati"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junghwa","family":"Lee","sequence":"additional","affiliation":[{"name":"Emory Vaccine Center, Emory University School of Medicine","place":["Atlanta"]},{"name":"Department of Microbiology and Immunology, Emory University School of Medicine","place":["Atlanta"]},{"name":"Viral Immunology Laboratory, Institut Pasteur Korea","place":["Seongnam, Republic of Korea"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rajesh M.","family":"Valanparambil","sequence":"additional","affiliation":[{"name":"Emory Vaccine Center, Emory University School of Medicine","place":["Atlanta"]},{"name":"Department of Microbiology and Immunology, Emory University School of Medicine","place":["Atlanta"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akil","family":"Akhtar","sequence":"additional","affiliation":[{"name":"Emory Vaccine Center, Emory University School of Medicine","place":["Atlanta"]},{"name":"Department of Microbiology and Immunology, Emory University School of Medicine","place":["Atlanta"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohammad Affan","family":"Khan","sequence":"additional","affiliation":[{"name":"Emory Vaccine Center, Emory University School of Medicine","place":["Atlanta"]},{"name":"Department of Microbiology and Immunology, Emory University School of Medicine","place":["Atlanta"]},{"name":"Immunology Laboratory, Department of Biomedical Engineering, Indian Institute of Technology Ropar","place":["Rupnagar, India"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhipeng","family":"Peng","sequence":"additional","affiliation":[{"name":"Emory Vaccine Center, Emory University School of Medicine","place":["Atlanta"]},{"name":"Department of Microbiology and Immunology, Emory University School of Medicine","place":["Atlanta"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yinghong","family":"Hu","sequence":"additional","affiliation":[{"name":"Emory Vaccine Center, Emory University School of Medicine","place":["Atlanta"]},{"name":"Department of Microbiology and Immunology, Emory University School of Medicine","place":["Atlanta"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel T.","family":"McManus","sequence":"additional","affiliation":[{"name":"Emory Vaccine Center, Emory University School of Medicine","place":["Atlanta"]},{"name":"Department of Microbiology and Immunology, Emory University School of Medicine","place":["Atlanta"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ilham","family":"Bahhar","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology, Pelotonia Institute for Immuno-Oncology, The Ohio State University Comprehensive Cancer Center, College of Medicine, The Ohio State University Wexner Medical Center","place":["Columbus"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas","family":"Wieland","sequence":"additional","affiliation":[{"name":"Emory Vaccine Center, Emory University School of Medicine","place":["Atlanta"]},{"name":"Department of Microbiology and Immunology, Emory University School of Medicine","place":["Atlanta"]},{"name":"Department of Otolaryngology, Pelotonia Institute for Immuno-Oncology, The Ohio State University Comprehensive Cancer Center, College of Medicine, The Ohio State University Wexner Medical Center","place":["Columbus"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carl W.","family":"Davis","sequence":"additional","affiliation":[{"name":"Emory Vaccine Center, Emory University School of Medicine","place":["Atlanta"]},{"name":"Department of Microbiology and Immunology, Emory University School of Medicine","place":["Atlanta"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0757-3106","authenticated-orcid":false,"given":"Suresh S.","family":"Ramalingam","sequence":"additional","affiliation":[{"name":"Winship Cancer Institute, Emory University School of Medicine","place":["Atlanta"]},{"name":"Department of Hematology and Medical Oncology, Emory University School of Medicine","place":["Atlanta"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arlene H.","family":"Sharpe","sequence":"additional","affiliation":[{"name":"Department of Immunology, Blavatnik Institute, Harvard Medical School","place":["Boston"]},{"name":"Gene Lay Institute of Immunology and Inflammation of Brigham and Women\u2018s Hospital, Massachusetts General Hospital and Harvard Medical School","place":["Boston"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2024-9041","authenticated-orcid":false,"given":"Jeffrey V.","family":"Ravetch","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Genetics and Immunology, The Rockefeller University","place":["New York"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7210-5616","authenticated-orcid":false,"given":"Gordon J.","family":"Freeman","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Dana-Farber Cancer Institute","place":["Boston"]},{"name":"Department of Medicine, Harvard Medical School","place":["Boston"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rafi","family":"Ahmed","sequence":"additional","affiliation":[{"name":"Emory Vaccine Center, Emory University School of Medicine","place":["Atlanta"]},{"name":"Department of Microbiology and Immunology, Emory University School of Medicine","place":["Atlanta"]},{"name":"Department of Hematology and Medical Oncology, Emory University School of Medicine","place":["Atlanta"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2026,4,8]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.aar4060"},{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/nri.2017.112"},{"key":"e_1_3_4_3_2","unstructured":"CR Institute Regulatory approval timeline of active immunotherapies (2025). https:\/\/www.cancerresearch.org\/regulatory-approval-timeline-of-active-immunotherapies. Accessed 14 November 2025."},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-pathol-042020-042741"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41568-019-0116-x"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20130573"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2015.08.004"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2018.02.010"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2019.00292"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20130579"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1118948"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.1038\/nri2206"},{"key":"e_1_3_4_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.it.2014.05.002"},{"key":"e_1_3_4_14_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2012-01-380121"},{"key":"e_1_3_4_15_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2008-09-179754"},{"key":"e_1_3_4_16_2","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2249.1996.d01-876.x"},{"key":"e_1_3_4_17_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2014.02.041"},{"key":"e_1_3_4_18_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00262-018-2160-x"},{"key":"e_1_3_4_19_2","doi-asserted-by":"publisher","DOI":"10.1136\/jitc-2021-003735"},{"key":"e_1_3_4_20_2","unstructured":"I. AnaptysBio Anaptys announces positive rosnilimab data updated through six months in robust phase 2b trial in RA (2025). https:\/\/ir.anaptysbio.com\/news-releases\/news-release-details\/anaptys-announces-positive-rosnilimab-data-updated-through-six\/. Accessed 14 November 2025."},{"key":"e_1_3_4_21_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaut.2024.103339"},{"key":"e_1_3_4_22_2","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.152468"},{"key":"e_1_3_4_23_2","doi-asserted-by":"publisher","DOI":"10.1093\/ecco-jcc\/jjad212.0121"},{"key":"e_1_3_4_24_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-022-05673-2"},{"key":"e_1_3_4_25_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2102164118"},{"key":"e_1_3_4_26_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2209856"},{"key":"e_1_3_4_27_2","doi-asserted-by":"publisher","DOI":"10.1126\/sciimmunol.add4947"},{"key":"e_1_3_4_28_2","unstructured":"I. AnaptysBio Anaptys announces new positive phase 2b trial results for rosnilimab in rheumatoid arthritis at ACR late-breaking oral presentation (2025). https:\/\/ir.anaptysbio.com\/news-releases\/news-release-details\/anaptys-announces-new-positive-phase-2b-trial-results-rosnilimab. Accessed 14 November 2025."},{"key":"e_1_3_4_29_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2018.11.054"},{"key":"e_1_3_4_30_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41416-018-0296-2"},{"key":"e_1_3_4_31_2","doi-asserted-by":"publisher","DOI":"10.1158\/2326-6066.CIR-15-0151"},{"key":"e_1_3_4_32_2","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-18-2311"},{"key":"e_1_3_4_33_2","doi-asserted-by":"publisher","DOI":"10.1128\/jvi.68.12.8056-8063.1994"},{"key":"e_1_3_4_34_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20132577"},{"key":"e_1_3_4_35_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature04444"},{"key":"e_1_3_4_36_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature19330"},{"key":"e_1_3_4_37_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2015.01.009"},{"key":"e_1_3_4_38_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2015.01.005"},{"key":"e_1_3_4_39_2","doi-asserted-by":"publisher","DOI":"10.1126\/sciimmunol.aao3125"},{"key":"e_1_3_4_40_2","doi-asserted-by":"publisher","DOI":"10.1038\/74704"},{"key":"e_1_3_4_41_2","doi-asserted-by":"publisher","DOI":"10.1158\/2326-6066.CIR-13-0013"},{"key":"e_1_3_4_42_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.179.5.3351"},{"key":"e_1_3_4_43_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1101629"},{"key":"e_1_3_4_44_2","doi-asserted-by":"publisher","DOI":"10.1002\/art.27233"},{"key":"e_1_3_4_45_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.93.18.9730"},{"key":"e_1_3_4_46_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2014.06.010"},{"key":"e_1_3_4_47_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrclinonc.2016.217"},{"key":"e_1_3_4_48_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20040119"},{"key":"e_1_3_4_49_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1402988"},{"key":"e_1_3_4_50_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI70972"},{"key":"e_1_3_4_51_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2015.03.005"},{"key":"e_1_3_4_52_2","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2014.005"},{"key":"e_1_3_4_53_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.174.2.817"},{"key":"e_1_3_4_54_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1917298117"},{"key":"e_1_3_4_55_2","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.19.00709"},{"key":"e_1_3_4_56_2","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-16-1741"},{"key":"e_1_3_4_57_2","doi-asserted-by":"publisher","DOI":"10.1001\/jamaoncol.2018.3676"},{"key":"e_1_3_4_58_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41571-018-0111-2"},{"key":"e_1_3_4_59_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41416-020-0975-7"},{"key":"e_1_3_4_60_2","doi-asserted-by":"publisher","DOI":"10.1093\/annonc\/mdz123"},{"key":"e_1_3_4_61_2","doi-asserted-by":"publisher","DOI":"10.1007\/s10120-018-00922-8"},{"key":"e_1_3_4_62_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1235214"},{"key":"e_1_3_4_63_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1235208"},{"key":"e_1_3_4_64_2","doi-asserted-by":"publisher","DOI":"10.1038\/icb.2012.9"},{"key":"e_1_3_4_65_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00262-012-1331-4"}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.2427192123","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,8]],"date-time":"2026-04-08T17:05:04Z","timestamp":1775667904000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/10.1073\/pnas.2427192123"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4,8]]},"references-count":65,"journal-issue":{"issue":"15","published-print":{"date-parts":[[2026,4,14]]}},"alternative-id":["10.1073\/pnas.2427192123"],"URL":"https:\/\/doi.org\/10.1073\/pnas.2427192123","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,4,8]]},"assertion":[{"value":"2024-12-29","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-03-09","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-04-08","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e2427192123"}}