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


A Corrigendum to this article was published on 12 June 2013

This article has been updated


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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Figure 1: CD8αα+, but not CD8α+β+, T cells persist at the DEJ in human HSV-2 infection.
Figure 2: Tissue residence and effector function of DEJ CD8αα+ T cells in post-healed tissue.
Figure 3: DEJ CD8 cells in early containment during asymptomatic HSV-2 reactivation.
Figure 4: Characteristics of DEJ CD8 cell TCRβ repertoire.

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  • 12 June 2013

    Nature 497, 494–497 (2013); doi:10.1038/nature12110 In Fig. 2a of our Letter, the label ‘CXCR7’ should be ‘CXCR6’, and the label ‘CXCR8’ should be ‘CXCR7’. This error has been corrected in the HTML and PDF versions of the paper.


  1. Zhu, J. et al. Virus-specific CD8+ T cells accumulate near sensory nerve endings in genital skin during subclinical HSV-2 reactivation. J. Exp. Med. 204, 595–603 (2007)

    Article  CAS  Google Scholar 

  2. Zhu, J. et al. Persistence of HIV-1 receptor-positive cells after HSV-2 reactivation is a potential mechanism for increased HIV-1 acquisition. Nature Med. 15, 886–892 (2009)

    Article  CAS  Google Scholar 

  3. Wald, A., Zeh, J., Selke, S., Ashley, R. L. & Corey, L. Virologic characteristics of subclinical and symptomatic genital herpes infections. N. Engl. J. Med. 333, 770–775 (1995)

    Article  CAS  Google Scholar 

  4. Wald, A. et al. Reactivation of genital herpes simplex virus type 2 infection in asymptomatic seropositive persons. N. Engl. J. Med. 342, 844–850 (2000)

    Article  CAS  Google Scholar 

  5. Mark, K. E. et al. Rapidly cleared episodes of herpes simplex virus reactivation in immunocompetent adults. J. Infect. Dis. 198, 1141–1149 (2008)

    Article  Google Scholar 

  6. Hayday, A., Theodoridis, E., Ramsburg, E. & Shires, J. Intraepithelial lymphocytes: exploring the Third Way in immunology. Nature Immunol. 2, 997–1003 (2001)

    Article  CAS  Google Scholar 

  7. Huang, Y. et al. Mucosal memory CD8+ T cells are selected in the periphery by an MHC class I molecule. Nature Immunol. 12, 1086–1095 (2011)

    Article  CAS  Google Scholar 

  8. Matloubian, M. et al. Lymphocyte egress from thymus and peripheral lymphoid organs is dependent on S1P receptor 1. Nature 427, 355–360 (2004)

    Article  ADS  CAS  Google Scholar 

  9. Bromley, S. K., Thomas, S. Y. & Luster, A. D. Chemokine receptor CCR7 guides T cell exit from peripheral tissues and entry into afferent lymphatics. Nature Immunol. 6, 895–901 (2005)

    Article  CAS  Google Scholar 

  10. Debes, G. F. et al. Chemokine receptor CCR7 required for T lymphocyte exit from peripheral tissues. Nature Immunol. 6, 889–894 (2005)

    Article  CAS  Google Scholar 

  11. Chi, H. & Flavell, R. A. Cutting edge: regulation of T cell trafficking and primary immune responses by sphingosine 1-phosphate receptor 1. J. Immunol. 174, 2485–2488 (2005)

    Article  CAS  Google Scholar 

  12. Peng, T. et al. An effector phenotype of CD8+ T cells at the junction epithelium during clinical quiescence of herpes simplex virus 2 infection. J. Virol. 86, 10587–10596 (2012)

    Article  CAS  Google Scholar 

  13. Schiffer, J. T. et al. Mucosal host immune response predicts the severity and duration of herpes simplex virus-2 genital tract shedding episodes. Proc. Natl Acad. Sci. USA 107, 18973–18978 (2010)

    Article  ADS  CAS  Google Scholar 

  14. Schiffer, J. T. et al. Frequent release of low amounts of herpes simplex virus from neurons: results of a mathematical model. Sci. Transl Med. 1, 7ra16 (2009)

    Article  ADS  Google Scholar 

  15. Robins, H. S. et al. Comprehensive assessment of T-cell receptor β-chain diversity in αβ T cells. Blood 114, 4099–4107 (2009)

    Article  CAS  Google Scholar 

  16. Tilloy, F. et al. An invariant T cell receptor α chain defines a novel TAP-independent major histocompatibility complex class Ib-restricted αβ T cell subpopulation in mammals. J. Exp. Med. 189, 1907–1921 (1999)

    Article  CAS  Google Scholar 

  17. Le Bourhis, L. et al. Mucosal-associated invariant T cells: unconventional development and function. Trends Immunol. 32, 212–218 (2011)

    Article  CAS  Google Scholar 

  18. Jing, L. et al. Cross-presentation and genome-wide screening reveal candidate T cells antigens for a herpes simplex virus type 1 vaccine. J. Clin. Invest. 122, 654–673 (2012)

    Article  CAS  Google Scholar 

  19. Clark, R. A. et al. Skin effector memory T cells do not recirculate and provide immune protection in alemtuzumab-treated CTCL patients. Sci. Transl. Med. 4, 117ra7 (2012)

    Article  Google Scholar 

  20. Gebhardt, T. et al. Memory T cells in nonlymphoid tissue that provide enhanced local immunity during infection with herpes simplex virus. Nature Immunol. 10, 524–530 (2009)

    Article  MathSciNet  CAS  Google Scholar 

  21. Gebhardt, T. et al. Different patterns of peripheral migration by memory CD4+ and CD8+ T cells. Nature 477, 216–219 (2011)

    Article  ADS  CAS  Google Scholar 

  22. Jiang, X. et al. Skin infection generates non-migratory memory CD8+ TRM cells providing global skin immunity. Nature 483, 227–231 (2012)

    Article  ADS  CAS  Google Scholar 

  23. Khanna, K. M., Bonneau, R. H., Kinchington, P. R. & Hendricks, R. L. Herpes simplex virus-specific memory CD8+ T cells are selectively activated and retained in latently infected sensory ganglia. Immunity 18, 593–603 (2003)

    Article  CAS  Google Scholar 

  24. Purwar, R. et al. Resident memory T cells (TRM) are abundant in human lung: diversity, function, and antigen specificity. PLoS ONE 6, e16245 (2011)

    Article  ADS  CAS  Google Scholar 

  25. Wakim, L. M., Woodward-Davis, A. & Bevan, M. J. Memory T cells persisting within the brain after local infection show functional adaptations to their tissue of residence. Proc. Natl Acad. Sci. USA 107, 17872–17879 (2010)

    Article  ADS  CAS  Google Scholar 

  26. Trautmann, L. et al. Selection of T cell clones expressing high-affinity public TCRs within human cytomegalovirus-specific CD8 T cell responses. J. Immunol. 175, 6123–6132 (2005)

    Article  CAS  Google Scholar 

  27. Cunningham, A. L., Turner, R. R., Miller, A. C., Para, M. F. & Merigan, T. C. Evolution of recurrent herpes simplex lesions. An immunohistologic study. J. Clin. Invest. 75, 226–233 (1985)

    Article  CAS  Google Scholar 

  28. Nakanishi, Y., Lu, B., Gerard, C. & Iwasaki, A. CD8+ T lymphocyte mobilization to virus-infected tissue requires CD4+ T-cell help. Nature 462, 510–513 (2009)

    Article  ADS  CAS  Google Scholar 

  29. Magaret, A. S., Wald, A., Huang, M. L., Selke, S. & Corey, L. Optimizing PCR positivity criterion for detection of herpes simplex virus DNA on skin and mucosa. J. Clin. Microbiol. 45, 1618–1620 (2007)

    Article  CAS  Google Scholar 

  30. Riddell, S. R. et al. Restoration of viral immunity in immunodeficient humans by the adoptive transfer of T cell clones. Science 257, 238–241 (1992)

    Article  ADS  CAS  Google Scholar 

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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.

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Authors and Affiliations



J.Z. and L.C. conceived the study and wrote the manuscript. J.Z. and T.P. developed the technology and analysed and interpreted the data. K.P., A.S.K., A.K., L.J. and K.D. performed the experiments. D.M.K. isolated HSV-2 reactive CD8+ T cells and peptide epitope used in the study. C.J. and A.W. directed human biopsy studies. H.R. contributed to TCR data analysis and interpretation. All authors contributed to the discussion.

Corresponding authors

Correspondence to Jia Zhu or Lawrence Corey.

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Competing interests

L.C. is on the scientific advisory board for, and hold stock (<1% of company) in, Immune Design Corp. H.R. is a co-founder of Adaptive Biotechnologies, owns stock and intellectual property of this company, and consults for the company. A.W. has received research support from NIH, Genocea Biosciences, Agenus, and Gilead Sciences, and has been a consultant to Aicuris GmbH. D.M.K. is a consultant for Agenus and EISAI. C.J. is conducting research with AiCuris GmbH, which is developing treatment for HSV.

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Zhu, J., Peng, T., Johnston, C. et al. Immune surveillance by CD8αα+ skin-resident T cells in human herpes virus infection. Nature 497, 494–497 (2013).

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