title: Phenotypic and functional characterization of herpes simplex virus glycoprotein B epitope-specific effector and memory CD8+ T cells from symptomatic and asymptomatic individuals with ocular herpes.
abstract: Herpes simplex virus 1 (HSV-1) glycoprotein B (gB)-specific CD8(+) T cells protect mice from herpes infection and disease. However, whether and which HSV-1 gB-specific CD8(+) T cells play a key role in the "natural" protection seen in HSV-1-seropositive healthy asymptomatic (ASYMP) individuals (who have never had clinical herpes disease) remain to be determined. In this study, we have dissected the phenotypes and the functions of HSV-1 gB-specific CD8(+) T cells from HLA-A*02:01 positive, HSV-1 seropositive ASYMP and symptomatic (SYMP) individuals (with a history of numerous episodes of recurrent ocular herpes disease). We found the following. (i) Healthy ASYMP individuals maintained a significantly higher proportion of differentiated HSV-1 gB-specific effector memory CD8(+) T cells (TEM cells) (CD45RA(low) CCR7(low) CD44(high) CD62L(low)). In contrast, SYMP patients had frequent less-differentiated central memory CD8(+) T cells (TCM cells) (CD45RA(low) CCR7(high) CD44(low) CD62L(high)). (ii) ASYMP individuals had significantly higher proportions of multifunctional effector CD8(+) T cells which responded mainly to gB342-350 and gB561-569 "ASYMP" epitopes, and simultaneously produced IFN-γ, CD107(a/b), granzyme B, and perforin. In contrast, effector CD8(+) T cells from SYMP individuals were mostly monofunctional and were directed mainly against nonoverlapping gB17-25 and gB183-191 "SYMP" epitopes. (iii) Immunization of an HLA-A*02:01 transgenic mouse model of ocular herpes with "ASYMP" CD8(+) TEM cell epitopes, but not with "SYMP" CD8(+) TCM cell epitopes, induced a strong CD8(+) T cell-dependent protective immunity against ocular herpes infection and disease. Our findings provide insights into the role of HSV-specific CD8(+) TEM cells in protection against herpes and should be considered in the development of an effective vaccine.
  
  
  OBJECTIVE
  A significantly higher proportion of differentiated and multifunctional HSV-1 gB-specific effector memory CD8(+) T cells (TEM cells) (CD45RA(low) CCR7(low) CD44(high) CD62L(low)) were found in healthy ASYMP individuals who are seropositive for HSV-1 but never had any recurrent herpetic disease, while there were frequent less-differentiated and monofunctional central memory CD8(+) T cells (TCM cells) (CD45RA(low) CCR7(high) CD44(low) CD62L(high)) in SYMP patients. Immunization with "ASYMP" CD8(+) TEM cell epitopes, but not with "SYMP" CD8(+) TCM cell epitopes, induced a strong protective HSV-specific CD8(+) T cell response in HLA-A*02:01 transgenic mice. These findings are important for the development of a safe and effective T cell-based herpes vaccine.
authors.affiliation: Laboratory of Cellular and Molecular Immunology, Gavin Herbert Eye Institute, University of California, Irvine, School of Medicine, Irvine, California, USA.
authors.forename: Arif A
authors.initials: AA
authors.lastname: Khan
authors.affiliation: Laboratory of Cellular and Molecular Immunology, Gavin Herbert Eye Institute, University of California, Irvine, School of Medicine, Irvine, California, USA.
authors.forename: Ruchi
authors.initials: R
authors.lastname: Srivastava
authors.affiliation: Laboratory of Cellular and Molecular Immunology, Gavin Herbert Eye Institute, University of California, Irvine, School of Medicine, Irvine, California, USA.
authors.forename: Doran
authors.initials: D
authors.lastname: Spencer
authors.affiliation: Laboratory of Cellular and Molecular Immunology, Gavin Herbert Eye Institute, University of California, Irvine, School of Medicine, Irvine, California, USA.
authors.forename: Sumit
authors.initials: S
authors.lastname: Garg
authors.affiliation: Laboratory of Cellular and Molecular Immunology, Gavin Herbert Eye Institute, University of California, Irvine, School of Medicine, Irvine, California, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Fremgen
authors.affiliation: Laboratory of Cellular and Molecular Immunology, Gavin Herbert Eye Institute, University of California, Irvine, School of Medicine, Irvine, California, USA.
authors.forename: Hawa
authors.initials: H
authors.lastname: Vahed
authors.affiliation: Laboratory of Cellular and Molecular Immunology, Gavin Herbert Eye Institute, University of California, Irvine, School of Medicine, Irvine, California, USA.
authors.forename: Patricia P
authors.initials: PP
authors.lastname: Lopes
authors.affiliation: Laboratory of Cellular and Molecular Immunology, Gavin Herbert Eye Institute, University of California, Irvine, School of Medicine, Irvine, California, USA.
authors.forename: Thanh T
authors.initials: TT
authors.lastname: Pham
authors.affiliation: Laboratory of Cellular and Molecular Immunology, Gavin Herbert Eye Institute, University of California, Irvine, School of Medicine, Irvine, California, USA.
authors.forename: Charlie
authors.initials: C
authors.lastname: Hewett
authors.affiliation: Laboratory of Cellular and Molecular Immunology, Gavin Herbert Eye Institute, University of California, Irvine, School of Medicine, Irvine, California, USA.
authors.forename: Jasmine
authors.initials: J
authors.lastname: Kuang
authors.affiliation: Laboratory of Cellular and Molecular Immunology, Gavin Herbert Eye Institute, University of California, Irvine, School of Medicine, Irvine, California, USA.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Ong
authors.affiliation: Laboratory of Cellular and Molecular Immunology, Gavin Herbert Eye Institute, University of California, Irvine, School of Medicine, Irvine, California, USA.
authors.forename: Lei
authors.initials: L
authors.lastname: Huang
authors.affiliation: Stem Cell Research Center, University of California, Irvine, Irvine, California, USA.
authors.forename: Vanessa M
authors.initials: VM
authors.lastname: Scarfone
authors.affiliation: Laboratory of Cellular and Molecular Immunology, Gavin Herbert Eye Institute, University of California, Irvine, School of Medicine, Irvine, California, USA.
authors.forename: Anthony B
authors.initials: AB
authors.lastname: Nesburn
authors.affiliation: Laboratory of Cellular and Molecular Immunology, Gavin Herbert Eye Institute, University of California, Irvine, School of Medicine, Irvine, California, USA Virology Research, Gavin Herbert Eye Institute and Department of Ophthalmology, University of California, Irvine, School of Medicine, Irvine, California, USA Department of Microbiology and Molecular Genetics, University of California, Irvine, School of Medicine, Irvine, California, USA Center for Virus Research, University of California, Irvine, Irvine, California, USA.
authors.forename: Steven L
authors.identifier: http://orcid.org/0000-0001-8509-5229
authors.initials: SL
authors.lastname: Wechsler
authors.affiliation: Laboratory of Cellular and Molecular Immunology, Gavin Herbert Eye Institute, University of California, Irvine, School of Medicine, Irvine, California, USA Department of Molecular Biology & Biochemistry, University of California, Irvine, School of Medicine, Irvine, California, USA Institute for Immunology, University of California, Irvine, School of Medicine, Irvine, California, USA Lbenmoha@uci.edu.
authors.forename: Lbachir
authors.initials: L
authors.lastname: BenMohamed
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D058070:Asymptomatic Diseases; D018414:CD8-Positive T-Lymphocytes / Q000737:chemistry / Q000276:immunology*; D018984:Epitopes, T-Lymphocyte / Q000276:immunology*; D005260:Female; D006801:Humans; D016849:Keratitis, Herpetic / Q000276:immunology* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D014759:Viral Envelope Proteins / Q000276:immunology*; D055815:Young Adult
chemical_list: D018984:Epitopes, T-Lymphocyte; D014759:Viral Envelope Proteins; C040495:glycoprotein B, Simplexvirus