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

Nature. 2013 May 23;497(7450):494-7. doi: 10.1038/nature12110. Epub 2013 May 8.


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. 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • CD8-Positive T-Lymphocytes / cytology
  • CD8-Positive T-Lymphocytes / immunology*
  • Clone Cells / cytology
  • Clone Cells / immunology
  • Herpes Genitalis / immunology*
  • Herpes Genitalis / virology
  • Herpesvirus 2, Human / immunology*
  • Humans
  • Immunologic Memory / immunology
  • Immunologic Surveillance*
  • Receptors, Antigen, T-Cell, alpha-beta / immunology
  • Receptors, Antigen, T-Cell, alpha-beta / metabolism
  • Skin / cytology*
  • Skin / immunology*


  • Receptors, Antigen, T-Cell, alpha-beta