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 cleared1,2. 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 β-chain (TCRβ) genotyping on sequential genital skin biopsies, we show that CD8αα+ T cells are the dominant resident population of DEJ CD8+ T cells that persist at the site of previous 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 TCR β-chain repertoire reveals that the DEJ CD8αα+ T cells are oligoclonal with diverse usage of TCR variable-β 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 CD8αα+ T cells. These studies indicate that DEJ CD8αα+ 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 CD8αα+ T cells may be a critical component for developing effective vaccines against skin and mucosal infections.
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Gene Expression Omnibus
We thank M. Huang, H. Xie, J. Vazquez and D. McDonald for technical assistance; M. Prlic and C. Desmarais for discussion and reading the manuscript and M. Miner for editing. We also thank our study participants and S. Kuntz and M. Stern for clinical assistance. This work was supported by grants from the National Institutes of Health (R37AI042528, R01AI04252815, P01AI030731 and R56AI093746) and the James B. Pendleton Charitable Trust.
This file contains Supplementary Figures 1-5 and Supplementary Tables 1-5.