Immune surveillance by CD8αα+ skin-resident T cells in human herpes virus infection

Most herpes simplex virus 2 (HSV-2) reactivations in humans are subclinical and associated with rapid expansion and containment of virus. Previous studies have shown that CD8(+) T cells persist in genital skin and mucosa at the dermal-epidermal junction (DEJ)-the portal of neuronal release of reactivating virus-for prolonged time periods after herpes lesions are cleared(1,2). The phenotype and function of this persistent CD8(+) T-cell population remain unknown. Here, using cell-type-specific laser capture microdissection, transcriptional profiling and T-cell antigen receptor beta-chain (TCR beta) genotyping on sequential genital skin biopsies, we show that CD8 alpha alpha(+) T cells are the dominant resident population of DEJ CD8(+) T cells that persist at the site of previous HSV-2 reactivation. CD8 alpha alpha(+) T cells located at the DEJ lack chemokine-receptor expression required for lymphocyte egress and recirculation, express gene signatures of T-cell activation and antiviral activity, and produce cytolytic granules during clinical and virological quiescent time periods. Sequencing of the TCR beta-chain repertoire reveals that the DEJ CD8 alpha alpha(+) T cells are oligoclonal with diverse usage of TCR variable-beta genes, which differ from those commonly described for mucosa-associated invariant T cells and natural killer T cells. Dominant clonotypes are shown to overlap among multiple recurrences over a period of two-and-a-half years. Episodes of rapid asymptomatic HSV-2 containment were also associated with a high CD8 effector-to-target ratio and focal enrichment of CD8 alpha alpha(+) T cells. These studies indicate that DEJ CD8 alpha alpha(+) T cells are tissue-resident cells that seem to have a fundamental role in immune surveillance and in initial containment of HSV-2 reactivation in human peripheral tissue. Elicitation of CD8 alpha alpha(+) T cells may be a critical component for developing effective vaccines against skin and mucosal infections.