{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,26]],"date-time":"2026-02-26T23:25:48Z","timestamp":1772148348678,"version":"3.50.1"},"reference-count":49,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2025,4,24]],"date-time":"2025-04-24T00:00:00Z","timestamp":1745452800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Institutes of Health Research R01","award":["EY019896"],"award-info":[{"award-number":["EY019896"]}]},{"name":"National Institutes of Health Research R01","award":["EY024618"],"award-info":[{"award-number":["EY024618"]}]},{"name":"National Institutes of Health Research R01","award":["AI150091"],"award-info":[{"award-number":["AI150091"]}]},{"name":"National Institutes of Health Research R01","award":["AI143348"],"award-info":[{"award-number":["AI143348"]}]},{"name":"The Discovery Center for Eye Research","award":["EY019896"],"award-info":[{"award-number":["EY019896"]}]},{"name":"The Discovery Center for Eye Research","award":["EY024618"],"award-info":[{"award-number":["EY024618"]}]},{"name":"The Discovery Center for Eye Research","award":["AI150091"],"award-info":[{"award-number":["AI150091"]}]},{"name":"The Discovery Center for Eye Research","award":["AI143348"],"award-info":[{"award-number":["AI143348"]}]},{"name":"RPB Unrestricted Grant","award":["EY019896"],"award-info":[{"award-number":["EY019896"]}]},{"name":"RPB Unrestricted Grant","award":["EY024618"],"award-info":[{"award-number":["EY024618"]}]},{"name":"RPB Unrestricted Grant","award":["AI150091"],"award-info":[{"award-number":["AI150091"]}]},{"name":"RPB Unrestricted Grant","award":["AI143348"],"award-info":[{"award-number":["AI143348"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>Herpes simplex virus (HSV)-specific CD8+ T cells protect mice from herpes infection and disease. However, the phenotype and function of HSV-specific CD8+ T cells that play a key role in the \u201cnatural\u201d protection seen in HSV-1-seropositive healthy asymptomatic (ASYMP) patients (who have never had clinical herpes disease) remain to be determined. We previously reported that symptomatic (SYMP) patients (who have frequent bouts of recurrent ocular herpes disease) had more undifferentiated and dysfunctional HSV-specific CD8+ T cells. In contrast, healthy ASYMP individuals maintained a significantly higher proportion of differentiated polyfunctional CD8+ T cells. Here, we report that HSV-specific CD8+ T cells from 10 SYMP patients, but not HSV-specific CD8+ T cells from 10 ASYMP patients, have phenotypic and functional characteristics of cellular senescence, including: (i) high frequency of senescent (CD57+) and exhausted (PD-1+) CD8+ T cells; (ii) late terminally differentiated (KLRG1+), non-proliferating CD8+ T cells; (iii) HSV-specific CD8+ T cells which decreased in number over time and were not homeostatically maintained, as indicated by a reduction in the number of CD127+CD8+ T cells; (iv) loss of the co-stimulatory molecule CD28 on HSV-specific CD8+ T cells; and (v) decreased production of effector molecules (granzyme B and perforin) by HSV-specific CD8+ T cells. Our findings provide insights into the role of senescence in HSV-specific CD8+ T cells in susceptibility to recurrent herpes and have implications for T-cell-based immunotherapeutic strategies against recurrent herpes in humans.<\/jats:p>","DOI":"10.3390\/v17050606","type":"journal-article","created":{"date-parts":[[2025,4,24]],"date-time":"2025-04-24T04:04:50Z","timestamp":1745467490000},"page":"606","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Dysfunctional Senescent Herpes Simplex Virus-Specific CD57+CD8+ T Cells Are Associated with Symptomatic Recurrent Ocular Herpes in Humans"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5410-2593","authenticated-orcid":false,"given":"Aziz A.","family":"Chentoufi","sequence":"first","affiliation":[{"name":"Laboratory of Cellular and Molecular Immunology, Gavin Herbert Eye Institute, School of Medicine, University of California Irvine, Irvine, CA 92697, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Arif A.","family":"Khan","sequence":"additional","affiliation":[{"name":"Laboratory of Cellular and Molecular Immunology, Gavin Herbert Eye Institute, School of Medicine, University of California Irvine, Irvine, CA 92697, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ruchi","family":"Srivastava","sequence":"additional","affiliation":[{"name":"Laboratory of Cellular and Molecular Immunology, Gavin Herbert Eye Institute, School of Medicine, University of California Irvine, Irvine, CA 92697, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sweta","family":"Karan","sequence":"additional","affiliation":[{"name":"Laboratory of Cellular and Molecular Immunology, Gavin Herbert Eye Institute, School of Medicine, University of California Irvine, Irvine, CA 92697, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yassir","family":"Lekbach","sequence":"additional","affiliation":[{"name":"Laboratory of Cellular and Molecular Immunology, Gavin Herbert Eye Institute, School of Medicine, University of California Irvine, Irvine, CA 92697, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hawa","family":"Vahed","sequence":"additional","affiliation":[{"name":"Laboratory of Cellular and Molecular Immunology, Gavin Herbert Eye Institute, School of Medicine, University of California Irvine, Irvine, CA 92697, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9468-2521","authenticated-orcid":false,"given":"Lbachir","family":"BenMohamed","sequence":"additional","affiliation":[{"name":"Laboratory of Cellular and Molecular Immunology, Gavin Herbert Eye Institute, School of Medicine, University of California Irvine, Irvine, CA 92697, USA"},{"name":"Department of Molecular Biology & Biochemistry, University of California Irvine, Irvine, CA 92697, USA"},{"name":"Institute for Immunology, School of Medicine, University of California Irvine, Irvine, CA 92697, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,4,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"6733","DOI":"10.1016\/j.vaccine.2014.10.002","article-title":"The Challenges and Opportunities for the Development of a T-Cell Epitope-Based Herpes Simplex Vaccine","volume":"32","author":"Kuo","year":"2014","journal-title":"Vaccine"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"715","DOI":"10.1016\/j.humimm.2014.04.016","article-title":"Associations of HLA-A, HLA-B and HLA-C Alleles Frequency with Prevalence of Herpes Simplex Virus Infections and Diseases Across Global Populations: Implication for the Development of an Universal CD8+ T-Cell Epitope-Based Vaccine","volume":"75","author":"Samandary","year":"2014","journal-title":"Hum. 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