title: Broadening the repertoire of functional herpes simplex virus type 1-specific CD8+ T cells reduces viral reactivation from latency in sensory ganglia.
abstract: 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 ± 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-IL-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-IL-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.
authors.affiliation: Department of Ophthalmology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: St Leger
authors.forename: Sohyun
authors.initials: S
authors.lastname: Jeon
authors.forename: Robert L
authors.initials: RL
authors.lastname: Hendricks
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000821:virology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000821:virology; D004195:Disease Models, Animal; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D005260:Female; D005434:Flow Cytometry; D017950:Ganglia, Sensory / Q000276:immunology / Q000821:virology*; D006561:Herpes Simplex / Q000276:immunology*; D018259:Herpesvirus 1, Human / Q000502:physiology; D016056:Immunodominant Epitopes / Q000276:immunology; D016753:Interleukin-10 / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D014775:Virus Activation / Q000276:immunology*; D017735:Virus Latency / Q000276:immunology*
chemical_list: D018984:Epitopes, T-Lymphocyte; D016056:Immunodominant Epitopes; D016753:Interleukin-10