Immune Surveillance by CD8αα(+) Skin Resident T Cells in Human Herpesvirus 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 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 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 receptor beta (TCRβ) genotyping on sequential genital skin biopsies, we show CD8αα(+) T cells are the dominant resident population of DEJ CD8(+) T cells that persist at the site of prior HSV-2 reactivation. CD8αα(+) 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 TCRβ chain repertoire revealed that the DEJ CD8αα(+) T cells are oligoclonal with diverse usage of TCR VB genes, which differ from those commonly described for MAIT and NKT cells. Dominant clonotypes overlapped among multiple recurrence episodes 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 CD8αα(+) T cells. These studies indicate DEJ CD8αα(+) T cells are tissue resident cells that appear to play a fundamental role in immune surveillance and in initial containment of HSV-2 reactivation in human peripheral tissue. Elicitation of CD8αα(+) T cells might be a critical component for developing effective vaccines against skin and mucosal infections.