Unique Type I Interferon, Expansion/Survival Cytokines, and JAK/STAT Gene Signatures of Multifunctional Herpes Simplex Virus-Specific Effector Memory CD8+ TEM Cells Are Associated with Asymptomatic Herpes in Humans

A large proportion of the world population harbors herpes simplex virus 1 (HSV-1), a major cause of infectious corneal blindness. HSV-specific CD8(+) T cells protect from herpesvirus 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 nonprotected symptomatic (SYMP) individuals, with a history of numerous episodes of recurrent herpetic disease, using the high-throughput digital NanoString nCounter system and flow cytometry. Interestingly, our results demonstrated that 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 multifunctional HSV-specific effector memory CD62L(low) CD44(high) CD8(+) T-EM cells were detected in ASYMP individuals compared to more of monofunctional central memory CD62L(high) CD44(high) CD8(+) T-CM 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 vaccines. IMPORTANCE A staggering number of the world population harbors herpes simplex virus 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 multifunctional HSVspecific effector memory CD8(+) T-EM cells were detected in ASYMP individuals. In contrast, nonprotected SYMP individuals had more central memory CD8(+) T-CM cells. The memory CD8(+) T-EM 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.