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Unique Type I Interferon, Expansion/Survival Cytokines and JAK/STAT Gene Signatures of Multi-Functional HSV-Specific Effector Memory CD8 + T EM Cells Are Associated with Asymptomatic Ocular Herpes in Humans.

Journal of Virology 2018 November 29
A large proportion of the world population harbors herpes simplex virus type 1 (HSV-1) a major cause of infectious corneal blindness. HSV-specific CD8+ T cells protect from herpes infection and disease. However, the genomic, phenotypic and functional characteristics of CD8+ T cells associated with the protection seen in asymptomatic (ASYMP) individuals, who despite being infected, never experienced any recurrent herpetic disease, remains to be fully elucidated. In this investigation, we compared the phenotype, function, and level of expression of a comprehensive panel of 579 immune genes of memory CD8+ T cells, sharing the same HSV-1 epitope-specificities, and freshly isolated peripheral blood from well-characterized cohorts of protected ASYMP and non-protected symptomatic (SYMP) individuals, with a history of numerous episodes of recurrent herpetic disease using high throughput digital NanoString nCounter™ system and Flow Cytometry. Interestingly, our results demonstrated memory CD8+ T cells from ASYMP individuals expressed a unique set of genes involved in expansion and survival, type I interferon (IFN-I) and JAK/STAT pathways. Frequent multi-functional HSV-specific effector memory CD62Llow CD44high CD8+ TEM cells were detected in ASYMP individuals compared to more of mono-functional central memory CD62Lhigh CD44high CD8+ TCM cells in SYMP individuals. Shedding light on the genotype, phenotype, and function of antiviral CD8+ T cells from "naturally protected" ASYMP individuals will help design future T-cell based ocular herpes immunotherapeutic vaccine. IMPORTANCE A staggering number of the world population harbors herpes simplex virus type 1 (HSV-1) potentially leading to blinding recurrent herpetic disease. While the majority are asymptomatic (ASYMP) individuals who never experienced any recurrent herpetic disease, symptomatic (SYMP) individuals have a history of numerous episodes of recurrent ocular herpetic disease. This study elucidates the phenotype, the effector function, and the gene signatures of memory CD8+ T cell populations associated with protection seen in ASYMP individuals. Frequent multi-functional HSV-specific effector memory CD8+ TEM cells were detected in ASYMP individuals. In contrast, non-protected SYMP individuals had more of central memory CD8+ TCM cells. The memory CD8+ TEM cells from ASYMP individuals expressed unique gene signatures characterized by higher levels of type I interferon (IFN), expansion and expansion/survival cytokines and JAK/STAT pathways. Future studies on the genotype, phenotype, and function of antiviral CD8+ T cells from "naturally protected" ASYMP individuals will help in the potential design of T-cell based ocular herpes vaccines.

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