Asymptomatic HLA-A*02:01-restricted epitopes from herpes simplex virus glycoprotein B preferentially recall polyfunctional CD8 + T cells from seropositive asymptomatic individuals and protect HLA transgenic mice against ocular herpes

Xavier Dervillez, Huma Qureshi, Aziz A. Chentoufi, Arif A. Khan, Elizabeth Kritzer, David C. Yu, Oscar R. Diaz, Chetan Gottimukkala, Mina Kalantari, Maria C. Villacres, Vanessa M. Scarfone, Denise M. McKinney, John Sidney, Alessandro Sette, Anthony B. Nesburn, Steven L. Wechsler, Lbachir Ben Mohamed*

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

42 Citations (Scopus)

Abstract

Evidence from C57BL/6 mice suggests that CD8+ T cells, specific to the immunodominant HSV-1 glycoprotein B (gB) H-2b- restricted epitope (gB498-505), protect against ocular herpes infection and disease. However, the possible role of CD8+ T cells, specific to HLA-restricted gB epitopes, in protective immunity seen in HSV-1-seropositive asymptomatic (ASYMP) healthy individuals (who have never had clinical herpes) remains to be determined. In this study, we used multiple prediction algorithms to identify 10 potential HLA-A*02:01-restricted CD8+ T cell epitopes from the HSV-1 gB amino acid sequence. Six of these epitopes exhibited high-affinity binding to HLA-A*02:01 molecules. In 10 sequentially studied HLA-A*02:01-positive, HSV-1-seropositive ASYMP individuals, the most frequent, robust, and polyfunctional CD8+ T cell responses, as assessed by a combination of tetramer, IFN-γ-ELISPOT, CFSE proliferation, CD107a/b cytotoxic degranulation, and multiplex cytokine assays, were directed mainly against epitopes gB 342-350 and gB561-569. In contrast, in 10 HLA-A *02:01-positive, HSV-1-seropositive symptomatic (SYMP) individuals (with a history of numerous episodes of recurrent clinical herpes disease) frequent, but less robust, CD8+ T cell responses were directed mainly against nonoverlapping epitopes (gB183-191 and gB441-449). ASYMP individuals had a significantly higher proportion of HSV-gB-specific CD8+ T cells expressing CD107a/b degranulation marker and producing effector cytokines IL-2, IFN-γ, and TNF-α than did SYMP individuals. Moreover, immunization of a novel herpes-susceptible HLA-A*02:01 transgenic mouse model with ASYMP epitopes, but not with SYMP epitopes, induced strong CD8+ T cell-dependent protective immunity against ocular herpes infection and disease. These findings should guide the development of a safe and effective T cell-based herpes vaccine.

Original languageEnglish
Pages (from-to)5124-5138
Number of pages15
JournalJournal of Immunology
Volume191
Issue number10
DOIs
Publication statusPublished - 15 Nov 2013
Externally publishedYes

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