ABSTRACTHerpes 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 (TEMcells) (CD45RAlowCCR7lowCD44highCD62Llow). In contrast, SYMP patients had frequent less-differentiated central memory CD8+T cells (TCMcells) (CD45RAlowCCR7highCD44lowCD62Lhigh). (ii) ASYMP individuals had significantly higher proportions of multifunctional effector CD8+T cells which responded mainly to gB342–350and gB561–569“ASYMP” epitopes, and simultaneously produced IFN-γ, CD107a/b, granzyme B, and perforin. In contrast, effector CD8+T cells from SYMP individuals were mostly monofunctional and were directed mainly against nonoverlapping gB17–25and gB183–191“SYMP” epitopes. (iii) Immunization of an HLA-A*02:01 transgenic mouse model of ocular herpes with “ASYMP” CD8+TEMcell epitopes, but not with “SYMP” CD8+TCMcell 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+TEMcells in protection against herpes and should be considered in the development of an effective vaccine.IMPORTANCEA significantly higher proportion of differentiated and multifunctional HSV-1 gB-specific effector memory CD8+T cells (TEMcells) (CD45RAlowCCR7lowCD44highCD62Llow) 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 (TCMcells) (CD45RAlowCCR7highCD44lowCD62Lhigh) in SYMP patients. Immunization with “ASYMP” CD8+TEMcell epitopes, but not with “SYMP” CD8+TCMcell 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.
HLA-A02:01–Restricted Epitopes Identified from the Herpes Simplex Virus Tegument Protein VP11/12 Preferentially Recall Polyfunctional Effector Memory CD8+T Cells from Seropositive Asymptomatic Individuals and Protect Humanized HLA-A*02:01 Transgenic Mice against Ocular Herpes
