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 (T EM cells) (CD45RA low CCR7 low CD44 high CD62L low ). In contrast, SYMP patients had frequent less-differentiated central memory CD8 + T cells (T CM 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 gB 342–350 and gB 561–569 “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 gB 17–25 and gB 183–191 “SYMP” epitopes. (iii) Immunization of an HLA-A*02:01 transgenic mouse model of ocular herpes with “ASYMP” CD8 + T EM cell epitopes, but not with “SYMP” CD8 + T CM 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 + T EM cells in protection against herpes and should be considered in the development of an effective vaccine. IMPORTANCE A significantly higher proportion of differentiated and multifunctional HSV-1 gB-specific effector memory CD8 + T cells (T EM 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 (T CM cells) (CD45RA low CCR7 high CD44 low CD62L high ) in SYMP patients. Immunization with “ASYMP” CD8 + T EM cell epitopes, but not with “SYMP” CD8 + T CM 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.