{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,30]],"date-time":"2025-10-30T17:11:35Z","timestamp":1761844295168,"version":"3.40.2"},"reference-count":42,"publisher":"Oxford University Press (OUP)","issue":"5","license":[{"start":{"date-parts":[[2013,9,1]],"date-time":"2013-09-01T00:00:00Z","timestamp":1377993600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2013,9,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>A large proportion of the world population harbors HSV type 1 (HSV-1) in a latent state in their trigeminal ganglia (TG). TG-resident CD8+ T cells appear important for preventing HSV-1 reactivation from latency and recurrent herpetic disease. In C57BL\/6J mice, half of these cells are specific for an immunodominant epitope on HSV-1 glycoprotein B, whereas the other half are specific for 18 subdominant epitopes. In this study, we show that the CD8+ T cell dominance hierarchy in the TG established during acute infection is maintained during latency. However, CD8+ T cells specific for subdominant epitopes lose functionality, whereas those specific for the immunodominant epitope exhibit increased functionality in latently infected TG. Furthermore, we show that IL-10 produced by 16.4 \u00b1 2.8% of TG-resident CD4+ T cells maintains the immunodominance hierarchy in part through selective inhibition of subdominant CD8+ T cell proliferation. Upon systemic anti\u2013IL-10R Ab treatment, we observed a significant expansion of functional subdominant CD8+ T cells, resulting in significantly improved protection from viral reactivation. In fact, systemic anti\u2013IL-10R Ab treatment prevented viral reactivation in up to 50% of treated mice. Our results not only demonstrate that HSV-1 reactivation from latency can be prevented by expanding the repertoire of functional TG-resident CD8+ T cells, but also that IL-10R blockade might have therapeutic potential to reduce or eliminate recurrent herpetic disease.<\/jats:p>","DOI":"10.4049\/jimmunol.1300585","type":"journal-article","created":{"date-parts":[[2013,7,23]],"date-time":"2013-07-23T03:51:30Z","timestamp":1374551490000},"page":"2258-2265","source":"Crossref","is-referenced-by-count":38,"title":["Broadening the Repertoire of Functional Herpes Simplex Virus Type 1\u2013Specific CD8+ T Cells Reduces Viral Reactivation from Latency in Sensory Ganglia"],"prefix":"10.1093","volume":"191","author":[{"given":"Anthony J","family":"St. Leger","sequence":"first","affiliation":[{"name":"Department of Ophthalmology, University of Pittsburgh School of Medicine , Pittsburgh, PA 15213"},{"name":"Graduate Program in Immunology, University of Pittsburgh School of Medicine , Pittsburgh, PA 15213"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sohyun","family":"Jeon","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, University of Pittsburgh School of Medicine , Pittsburgh, PA 15213"},{"name":"Graduate Program in Immunology, University of Pittsburgh School of Medicine , Pittsburgh, PA 15213"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robert L","family":"Hendricks","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, University of Pittsburgh School of Medicine , Pittsburgh, PA 15213"},{"name":"Department of Immunology, University of Pittsburgh School of Medicine , Pittsburgh, PA 15213"},{"name":"Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine , Pittsburgh, PA 15213"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2013,9,1]]},"reference":[{"key":"2025032405235121700_r1","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1097\/00003226-200101000-00001","article-title":"Herpes simplex virus epidemiology and ocular importance","volume":"20","author":"Liesegang","year":"2001","journal-title":"Cornea"},{"key":"2025032405235121700_r2","doi-asserted-by":"crossref","first-page":"1139","DOI":"10.1128\/JVI.78.3.1139-1149.2004","article-title":"Specific histone tail modification and not DNA methylation is a determinant of herpes simplex virus type 1 latent gene expression","volume":"78","author":"Kubat","year":"2004","journal-title":"J. Virol."},{"key":"2025032405235121700_r3","doi-asserted-by":"crossref","first-page":"12508","DOI":"10.1128\/JVI.78.22.12508-12518.2004","article-title":"The herpes simplex virus type 1 latency-associated transcript (LAT) enhancer\/rcr is hyperacetylated during latency independently of LAT transcription","volume":"78","author":"Kubat","year":"2004","journal-title":"J. Virol."},{"key":"2025032405235121700_r4","doi-asserted-by":"crossref","first-page":"246","DOI":"10.1016\/j.bbagrm.2009.12.001","article-title":"Epigenetic regulation of latent HSV-1 gene expression","volume":"1799","author":"Bloom","year":"2010","journal-title":"Biochim. Biophys. Acta"},{"key":"2025032405235121700_r5","doi-asserted-by":"crossref","first-page":"2063","DOI":"10.1128\/JVI.80.4.2063-2068.2006","article-title":"Deacetylation of the herpes simplex virus type 1 latency-associated transcript (LAT) enhancer and a decrease in LAT abundance precede an increase in ICP0 transcriptional permissiveness at early times postexplant","volume":"80","author":"Amelio","year":"2006","journal-title":"J. Virol."},{"key":"2025032405235121700_r6","doi-asserted-by":"crossref","first-page":"3496","DOI":"10.1073\/pnas.0610847104","article-title":"Selective retention of herpes simplex virus-specific T cells in latently infected human trigeminal ganglia","volume":"104","author":"Verjans","year":"2007","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2025032405235121700_r7","doi-asserted-by":"crossref","first-page":"2179","DOI":"10.1016\/S0002-9440(10)63575-4","article-title":"Latent herpesvirus infection in human trigeminal ganglia causes chronic immune response","volume":"163","author":"Theil","year":"2003","journal-title":"Am. J. Pathol."},{"key":"2025032405235121700_r8","doi-asserted-by":"crossref","first-page":"593","DOI":"10.1016\/S1074-7613(03)00112-2","article-title":"Herpes simplex virus-specific memory CD8+ T cells are selectively activated and retained in latently infected sensory ganglia","volume":"18","author":"Khanna","year":"2003","journal-title":"Immunity"},{"key":"2025032405235121700_r9","doi-asserted-by":"crossref","first-page":"2760","DOI":"10.1128\/JVI.72.4.2760-2764.1998","article-title":"The quantity of latent viral DNA correlates with the relative rates at which herpes simplex virus types 1 and 2 cause recurrent genital herpes outbreaks","volume":"72","author":"Lekstrom-Himes","year":"1998","journal-title":"J. Virol."},{"key":"2025032405235121700_r10","doi-asserted-by":"crossref","first-page":"8157","DOI":"10.1128\/JVI.00474-07","article-title":"Rates of reactivation of latent herpes simplex virus from mouse trigeminal ganglia ex vivo correlate directly with viral load and inversely with number of infiltrating CD8+ T cells","volume":"81","author":"Hoshino","year":"2007","journal-title":"J. Virol."},{"key":"2025032405235121700_r11","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1146\/annurev.med.59.061606.095540","article-title":"Herpes simplex: insights on pathogenesis and possible vaccines","volume":"59","author":"Koelle","year":"2008","journal-title":"Annu. Rev. Med."},{"key":"2025032405235121700_r12","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1128\/CMR.16.1.96-113.2003","article-title":"Recent progress in herpes simplex virus immunobiology and vaccine research","volume":"16","author":"Koelle","year":"2003","journal-title":"Clin. Microbiol. Rev."},{"key":"2025032405235121700_r13","doi-asserted-by":"crossref","first-page":"17872","DOI":"10.1073\/pnas.1010201107","article-title":"Memory T cells persisting within the brain after local infection show functional adaptations to their tissue of residence","volume":"107","author":"Wakim","year":"2010","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2025032405235121700_r14","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1186\/2042-4280-2-5","article-title":"Circulating herpes simplex type 1 (HSV-1)-specific CD8+ T cells do not access HSV-1 latently infected trigeminal ganglia","volume":"2","author":"Himmelein","year":"2011","journal-title":"Herpesviridae"},{"key":"2025032405235121700_r15","doi-asserted-by":"crossref","first-page":"7619","DOI":"10.1128\/JVI.73.9.7619-7626.1999","article-title":"The cytotoxic T-cell response to herpes simplex virus type 1 infection of C57BL\/6 mice is almost entirely directed against a single immunodominant determinant","volume":"73","author":"Wallace","year":"1999","journal-title":"J. Virol."},{"key":"2025032405235121700_r16","doi-asserted-by":"crossref","first-page":"3927","DOI":"10.4049\/jimmunol.1003735","article-title":"Defining the herpes simplex virus-specific CD8+ T cell repertoire in C57BL\/6 mice","volume":"186","author":"St Leger","year":"2011","journal-title":"J. Immunol."},{"key":"2025032405235121700_r17","doi-asserted-by":"crossref","first-page":"1122","DOI":"10.1128\/jvi.69.2.1122-1131.1995","article-title":"Polymorphism within the herpes simplex virus (HSV) ribonucleotide reductase large subunit (ICP6) confers type specificity for recognition by HSV type 1-specific cytotoxic T lymphocytes","volume":"69","author":"Salvucci","year":"1995","journal-title":"J. Virol."},{"key":"2025032405235121700_r18","doi-asserted-by":"crossref","first-page":"8356","DOI":"10.4049\/jimmunol.177.12.8356","article-title":"Latent virus influences the generation and maintenance of CD8+ T cell memory","volume":"177","author":"Sheridan","year":"2006","journal-title":"J. Immunol."},{"key":"2025032405235121700_r19","doi-asserted-by":"crossref","first-page":"277","DOI":"10.4049\/jimmunol.0902373","article-title":"Early CD4(+) T cell help prevents partial CD8(+) T cell exhaustion and promotes maintenance of Herpes Simplex Virus 1 latency","volume":"184","author":"Frank","year":"2010","journal-title":"J. Immunol."},{"key":"2025032405235121700_r20","doi-asserted-by":"crossref","first-page":"2173","DOI":"10.4049\/jimmunol.1102719","article-title":"Maintenance of T cell function in the face of chronic antigen stimulation and repeated reactivation for a latent virus infection","volume":"188","author":"Mackay","year":"2012","journal-title":"J. Immunol."},{"key":"2025032405235121700_r21","doi-asserted-by":"crossref","first-page":"1459","DOI":"10.1084\/jem.191.9.1459","article-title":"CD8(+) T cells can block herpes simplex virus type 1 (HSV-1) reactivation from latency in sensory neurons","volume":"191","author":"Liu","year":"2000","journal-title":"J. Exp. Med."},{"key":"2025032405235121700_r22","doi-asserted-by":"crossref","first-page":"10339","DOI":"10.1128\/JVI.79.16.10339-10347.2005","article-title":"Gamma interferon can block herpes simplex virus type 1 reactivation from latency, even in the presence of late gene expression","volume":"79","author":"Decman","year":"2005","journal-title":"J. Virol."},{"key":"2025032405235121700_r23","doi-asserted-by":"crossref","first-page":"268","DOI":"10.1126\/science.1164164","article-title":"Noncytotoxic lytic granule-mediated CD8+ T cell inhibition of HSV-1 reactivation from neuronal latency","volume":"322","author":"Knickelbein","year":"2008","journal-title":"Science"},{"key":"2025032405235121700_r24","doi-asserted-by":"crossref","first-page":"1301","DOI":"10.1038\/nm1492","article-title":"Interleukin-10 determines viral clearance or persistence in vivo","volume":"12","author":"Brooks","year":"2006","journal-title":"Nat. Med."},{"key":"2025032405235121700_r25","doi-asserted-by":"crossref","first-page":"3018","DOI":"10.1073\/pnas.0914500107","article-title":"IL-10 directly suppresses CD4 but not CD8 T cell effector and memory responses following acute viral infection","volume":"107","author":"Brooks","year":"2010","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2025032405235121700_r26","doi-asserted-by":"crossref","first-page":"533","DOI":"10.1084\/jem.20071948","article-title":"IL-10 blockade facilitates DNA vaccine-induced T cell responses and enhances clearance of persistent virus infection","volume":"205","author":"Brooks","year":"2008","journal-title":"J. Exp. Med."},{"key":"2025032405235121700_r27","doi-asserted-by":"crossref","first-page":"2237","DOI":"10.1128\/JVI.01699-08","article-title":"Reevaluating the CD8 T-cell response to herpes simplex virus type 1: involvement of CD8 T cells reactive to subdominant epitopes","volume":"83","author":"Sheridan","year":"2009","journal-title":"J. Virol."},{"key":"2025032405235121700_r28","doi-asserted-by":"crossref","first-page":"20428","DOI":"10.1073\/pnas.0811139106","article-title":"IL-10 and PD-L1 operate through distinct pathways to suppress T-cell activity during persistent viral infection","volume":"105","author":"Brooks","year":"2008","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2025032405235121700_r29","doi-asserted-by":"crossref","first-page":"3583","DOI":"10.4049\/jimmunol.1001535","article-title":"IL-10 restricts memory T cell inflation during cytomegalovirus infection","volume":"185","author":"Jones","year":"2010","journal-title":"J. Immunol."},{"key":"2025032405235121700_r30","doi-asserted-by":"crossref","first-page":"14116","DOI":"10.1073\/pnas.1211910109","article-title":"Infected CD8\u03b1- dendritic cells are the predominant source of IL-10 during establishment of persistent viral infection","volume":"109","author":"Ng","year":"2012","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2025032405235121700_r31","doi-asserted-by":"crossref","first-page":"524","DOI":"10.1038\/ni.1718","article-title":"Memory T cells in nonlymphoid tissue that provide enhanced local immunity during infection with herpes simplex virus","volume":"10","author":"Gebhardt","year":"2009","journal-title":"Nat. Immunol."},{"key":"2025032405235121700_r32","doi-asserted-by":"crossref","first-page":"304","DOI":"10.1126\/science.330.6002.304","article-title":"Immunology. Painful failure of promising genital herpes vaccine","volume":"330","author":"Cohen","year":"2010","journal-title":"Science"},{"key":"2025032405235121700_r33","first-page":"1497","article-title":"Ocular safety and efficacy of an HSV-1 gD vaccine during primary and latent infection","volume":"31","author":"Nesburn","year":"1990","journal-title":"Invest. Ophthalmol. Vis. Sci."},{"key":"2025032405235121700_r34","doi-asserted-by":"crossref","first-page":"543","DOI":"10.1111\/j.1440-1711.2006.01469.x","article-title":"CTL response compensation for the loss of an immunodominant class I-restricted HSV-1 determinant","volume":"84","author":"Stock","year":"2006","journal-title":"Immunol. Cell Biol."},{"key":"2025032405235121700_r35","doi-asserted-by":"crossref","first-page":"3542","DOI":"10.4049\/jimmunol.157.8.3542","article-title":"Persistent cytokine expression in trigeminal ganglion latently infected with herpes simplex virus type 1","volume":"157","author":"Halford","year":"1996","journal-title":"J. Immunol."},{"key":"2025032405235121700_r36","doi-asserted-by":"crossref","first-page":"6277","DOI":"10.4049\/jimmunol.1300582","article-title":"PD-L1\/B7-H1 regulates the survival, but not the function of CD8+ T cells in herpes simplex virus type 1 latently infected trigeminal ganglia","volume":"190","author":"Jeon","year":"2013","journal-title":"J. Immunol."},{"key":"2025032405235121700_r37","doi-asserted-by":"crossref","first-page":"5986","DOI":"10.4049\/jimmunol.172.10.5986","article-title":"IL-10-secreting regulatory T cells do not express Foxp3 but have comparable regulatory function to naturally occurring CD4+CD25+ regulatory T cells","volume":"172","author":"Vieira","year":"2004","journal-title":"J. Immunol."},{"key":"2025032405235121700_r38","doi-asserted-by":"crossref","first-page":"1945","DOI":"10.4049\/jimmunol.159.4.1945","article-title":"Suppression of ongoing ocular inflammatory disease by topical administration of plasmid DNA encoding IL-10","volume":"159","author":"Daheshia","year":"1997","journal-title":"J. Immunol."},{"key":"2025032405235121700_r39","doi-asserted-by":"crossref","first-page":"2258","DOI":"10.4049\/jimmunol.153.5.2258","article-title":"Interleukin-10 treatment can suppress stromal keratitis induced by herpes simplex virus type 1","volume":"153","author":"Tumpey","year":"1994","journal-title":"J. Immunol."},{"key":"2025032405235121700_r40","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1016\/j.micpath.2004.09.003","article-title":"Interleukin-10 (IL-10) ameliorates corneal disease in a mouse model of recurrent herpetic keratitis","volume":"38","author":"Keadle","year":"2005","journal-title":"Microb. Pathog."},{"key":"2025032405235121700_r41","doi-asserted-by":"crossref","first-page":"1735","DOI":"10.4049\/jimmunol.1003456","article-title":"Controlling herpes simplex virus-induced ocular inflammatory lesions with the lipid-derived mediator resolvin E1","volume":"186","author":"Rajasagi","year":"2011","journal-title":"J. Immunol."},{"key":"2025032405235121700_r42","doi-asserted-by":"crossref","first-page":"2485","DOI":"10.1084\/jem.20061082","article-title":"IL-23 plays a key role in Helicobacter hepaticus-induced T cell-dependent colitis","volume":"203","author":"Kullberg","year":"2006","journal-title":"J. Exp. Med."}],"container-title":["The Journal of Immunology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/191\/5\/2258\/62513668\/1300585.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/191\/5\/2258\/62513668\/1300585.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,3,25]],"date-time":"2025-03-25T02:56:14Z","timestamp":1742871374000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jimmunol\/article\/191\/5\/2258\/7989780"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2013,9,1]]},"references-count":42,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2013,9,1]]}},"URL":"https:\/\/doi.org\/10.4049\/jimmunol.1300585","relation":{},"ISSN":["0022-1767","1550-6606"],"issn-type":[{"type":"print","value":"0022-1767"},{"type":"electronic","value":"1550-6606"}],"subject":[],"published-other":{"date-parts":[[2013,9]]},"published":{"date-parts":[[2013,9,1]]}}}