{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T09:20:27Z","timestamp":1788254427436,"version":"build-2803163510"},"reference-count":31,"publisher":"Wiley","issue":"11","license":[{"start":{"date-parts":[[2025,11,14]],"date-time":"2025-11-14T00:00:00Z","timestamp":1763078400000},"content-version":"vor","delay-in-days":13,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2025,11,1]],"date-time":"2025-11-01T00:00:00Z","timestamp":1761955200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100000001","name":"National Science Foundation","doi-asserted-by":"publisher","award":["R01AI66358"],"award-info":[{"award-number":["R01AI66358"]}],"id":[{"id":"10.13039\/100000001","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Eur J Immunol"],"published-print":{"date-parts":[[2025,11]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Chronic antigen exposure drives CD4\u207a T cell senescence, yet how autoimmunity and persistent viral infections differentially shape T cell differentiation and function remains unclear. Using cytomegalovirus (CMV) and rheumatoid arthritis (RA) as models of chronic immune activation, we performed high\u2010dimensional mass cytometry and functional assays to define their impact on CD4\u207a T cells. In CMV\u2010seropositive individuals, CD27\n                    <jats:sup>\u2212<\/jats:sup>\n                    CD28\n                    <jats:sup>\u2212<\/jats:sup>\n                    CD4\u207a T cells were abundant and exhibited a predominantly cytotoxic, nonproliferative phenotype. Only a minor fraction was CMV\u2010reactive, suggesting that bystander\u2010driven differentiation contributes to this subset. In the absence of CMV, senescent CD4\u207a T cells were infrequent and phenotypically distinct, though they still exhibited low proliferative capacity. EBV and HSV did not independently increase CD27\n                    <jats:sup>\u2212<\/jats:sup>\n                    CD28\n                    <jats:sup>\u2212<\/jats:sup>\n                    CD4\u207a T cell frequency. Similarly, RA had little effect on their abundance but instead tuned the functional quality of senescent cells. In CMV\u2010seropositive RA patients, senescent CD4\u207a T cells produced less pro\u2010inflammatory cytokines and showed impaired cytotoxic degranulation. Central memory CD4\u207a and CD27\n                    <jats:sup>\u2212<\/jats:sup>\n                    CD28\n                    <jats:sup>\u2212<\/jats:sup>\n                    CD8\u207a T cell functions were preserved, with no evidence for CMV reactivation, suggesting maintained viral control by unaffected T cell responses. These findings highlight distinct, nonredundant effects of CMV and RA on CD4\u207a T cell senescence and reveal RA\u2010specific functional defects in senescent CD4\u207a T cells.\n                  <\/jats:p>","DOI":"10.1002\/eji.70093","type":"journal-article","created":{"date-parts":[[2025,11,14]],"date-time":"2025-11-14T11:31:41Z","timestamp":1763119901000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Divergent Effects of Cytomegalovirus and Rheumatoid Arthritis on Senescent CD4\n                    <sup>+<\/sup>\n                    T Cells"],"prefix":"10.1002","volume":"55","author":[{"given":"Lea","family":"Williams","sequence":"first","affiliation":[{"name":"Department of Medicine Division of Rheumatology Perelman School of Medicine Institute for Immunology and Immune Health University of Pennsylvania Philadelphia Pennsylvania USA"},{"name":"Corporal Michael J Crescenz VA Medical Center Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-7912-5334","authenticated-orcid":false,"given":"Ali O.","family":"Saber","sequence":"additional","affiliation":[{"name":"Department of Medicine Division of Rheumatology Perelman School of Medicine Institute for Immunology and Immune Health University of Pennsylvania Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silina","family":"Awad","sequence":"additional","affiliation":[{"name":"Department of Medicine Division of Rheumatology Perelman School of Medicine Institute for Immunology and Immune Health University of Pennsylvania Philadelphia Pennsylvania USA"},{"name":"Corporal Michael J Crescenz VA Medical Center Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xi","family":"Su","sequence":"additional","affiliation":[{"name":"Department of Medicine Division of Rheumatology Perelman School of Medicine Institute for Immunology and Immune Health University of Pennsylvania Philadelphia Pennsylvania USA"},{"name":"Corporal Michael J Crescenz VA Medical Center Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7073-1154","authenticated-orcid":false,"given":"Asgar","family":"Ansari","sequence":"additional","affiliation":[{"name":"Department of Medicine Division of Rheumatology Perelman School of Medicine Institute for Immunology and Immune Health University of Pennsylvania Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruozhang","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Medicine Division of Rheumatology Perelman School of Medicine Institute for Immunology and Immune Health University of Pennsylvania Philadelphia Pennsylvania USA"},{"name":"Corporal Michael J Crescenz VA Medical Center Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hannah","family":"Jung","sequence":"additional","affiliation":[{"name":"Department of Medicine Division of Rheumatology Perelman School of Medicine Institute for Immunology and Immune Health University of Pennsylvania Philadelphia Pennsylvania USA"},{"name":"Corporal Michael J Crescenz VA Medical Center Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anupama","family":"Shahane","sequence":"additional","affiliation":[{"name":"Department of Medicine Division of Rheumatology Perelman School of Medicine Institute for Immunology and Immune Health University of Pennsylvania Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joshua F.","family":"Baker","sequence":"additional","affiliation":[{"name":"Department of Medicine Division of Rheumatology Perelman School of Medicine Institute for Immunology and Immune Health University of Pennsylvania Philadelphia Pennsylvania USA"},{"name":"Corporal Michael J Crescenz VA Medical Center Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0095-4755","authenticated-orcid":false,"given":"Laura F.","family":"Su","sequence":"additional","affiliation":[{"name":"Department of Medicine Division of Rheumatology Perelman School of Medicine Institute for Immunology and Immune Health University of Pennsylvania Philadelphia Pennsylvania USA"},{"name":"Corporal Michael J Crescenz VA Medical Center Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,11,14]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.10133"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.11445"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1186\/ar766"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.39419"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.0000131450.66017.B3"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.127.3.1024"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1111\/imr.13206"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.867189"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.173.3.1834"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.175.12.8218"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood\u20102002\u201007\u20102103"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.175.12.8415"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.07172\u201011"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1038\/nm.2612"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2020.05.017"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20091918"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586\u2010018\u20100694\u2010x"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.abe3348"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1907883116"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1002\/cyto.a.22271"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.1002\/cyto.a.24350"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.1086\/508173"},{"key":"e_1_2_9_24_1","first-page":"1659","volume-title":"A 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