title: CD8+ T Cells Play a Bystander Role in Mice Latently Infected with Herpes Simplex Virus 1.
abstract: Based on an explant reactivation model, it has been proposed that CD8(+) T cells maintain latency in trigeminal ganglia (TG) of mice latently infected with herpes simplex virus 1 (HSV-1) [T. Liu, K. M. Khanna, X. Chen, D. J. Fink, and R. L. Hendricks, J Exp Med 191:1459-1466, 2000, doi:10.1084/jem.191.9.1459; K. M. Khanna, R. H. Bonneau, P. R. Kinchington, and R. L. Hendricks, Immunity 18:593-603, 2003, doi:10.1016/S1074-7613(03)00112-2]. In those studies, BALB/c mice were ocularly infected with an avirulent HSV-1 strain (RE) after corneal scarification. However, in our studies, we typically infect mice with a virulent HSV-1 strain (McKrae) that does not require corneal scarification. Using a combination of knockout mice, adoptive transfers, and depletion studies, we recently found that CD8α(+) dendritic cells (DCs) contribute to HSV-1 latency and reactivation in TG of ocularly infected mice (K. R. Mott, S. J. Allen, M. Zandian, B. Konda, B. G. Sharifi, C. Jones, S. L. Wechsler, T. Town, and H. Ghiasi, PLoS One 9:e93444, 2014, doi:10.1371/journal.pone.0093444). This suggested that CD8(+) T cells might not be the major regulators of HSV-1 latency in the mouse TG. To investigate this iconoclastic possibility, we used a blocking CD8 antibody and CD8(+) T cells in reactivated TG explants from mice latently infected with (i) the avirulent HSV-1 strain RE following corneal scarification or (ii) the virulent HSV-1 strain McKrae without corneal scarification. Independently of the strain or approach, our results show that CD8α(+) DCs, not CD8(+) T cells, drive latency and reactivation. In addition, adoptive transfer of CD8(+) T cells from wild-type (wt) mice to CD8α(-/-) mice did not restore latency to the level for wt mice or wt virus. In the presence of latency-associated transcript (LAT((+)); wt virus), CD8(+) T cells seem to play a bystander role in the TG. These bystander T cells highly express PD-1, most likely due to the presence of CD8α(+) DCs. Collectively, these results support the notion that CD8(+) T cells do not play a major role in maintaining HSV-1 latency and reactivation.
  
  
  
  This study addresses a fundamentally important and widely debated issue in the field of HSV latency-reactivation. In this article, we directly compare the effects of anti-CD8 antibody, CD8(+) T cells, LAT, and CD8α(+) DCs in blocking explant reactivation in TG of mice latently infected with avirulent or virulent HSV-1. Our data suggest that CD8(+) T cells are not responsible for an increase or maintenance of latency in ocularly infected mice. However, they seem to play a bystander role that correlates with the presence of LAT, higher subclinical reactivation levels, and higher PD-1 expression levels.
authors.affiliation: Center for Neurobiology and Vaccine Development, Ophthalmology Research, Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, California, USA.
authors.forename: Kevin R
authors.initials: KR
authors.lastname: Mott
authors.affiliation: Zilkha Neurogenetic Institute, Department of Physiology & Biophysics, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
authors.forename: David
authors.initials: D
authors.lastname: Gate
authors.affiliation: Center for Neurobiology and Vaccine Development, Ophthalmology Research, Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, California, USA.
authors.forename: Harry H
authors.initials: HH
authors.lastname: Matundan
authors.affiliation: Zilkha Neurogenetic Institute, Department of Physiology & Biophysics, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
authors.forename: Yasamin N
authors.initials: YN
authors.lastname: Ghiasi
authors.affiliation: Zilkha Neurogenetic Institute, Department of Physiology & Biophysics, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
authors.forename: Terrence
authors.initials: T
authors.lastname: Town
authors.affiliation: Center for Neurobiology and Vaccine Development, Ophthalmology Research, Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, California, USA ghiasih@cshs.org.
authors.forename: Homayon
authors.initials: H
authors.lastname: Ghiasi
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D003713:Dendritic Cells / Q000737:chemistry / Q000276:immunology*; D005123:Eye / Q000821:virology; D018259:Herpesvirus 1, Human / Q000502:physiology*; D016849:Keratitis, Herpetic / Q000276:immunology* / Q000821:virology*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D061026:Programmed Cell Death 1 Receptor / Q000235:genetics; D012668:Trigeminal Ganglion / Q000821:virology*; D014775:Virus Activation; D017735:Virus Latency
chemical_list: C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor