Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

A vaccine strategy that protects against genital herpes by establishing local memory T cells

Abstract

Most successful existing vaccines rely on neutralizing antibodies, which may not require specific anatomical localization of B cells. However, efficacious vaccines that rely on T cells for protection have been difficult to develop, as robust systemic memory T-cell responses do not necessarily correlate with host protection1. In peripheral sites, tissue-resident memory T cells provide superior protection compared to circulating memory T cells2,3. Here we describe a simple and non-inflammatory vaccine strategy that enables the establishment of a protective memory T-cell pool within peripheral tissue. The female genital tract, which is a portal of entry for sexually transmitted infections, is an immunologically restrictive tissue that prevents entry of activated T cells in the absence of inflammation or infection4. To overcome this obstacle, we developed a vaccine strategy that we term ‘prime and pull’ to establish local tissue-resident memory T cells at a site of potential viral exposure. This approach relies on two steps: conventional parenteral vaccination to elicit systemic T-cell responses (prime), followed by recruitment of activated T cells by means of topical chemokine application to the restrictive genital tract (pull), where such T cells establish a long-term niche and mediate protective immunity. In mice, prime and pull protocol reduces the spread of infectious herpes simplex virus 2 into the sensory neurons and prevents development of clinical disease. These results reveal a promising vaccination strategy against herpes simplex virus 2, and potentially against other sexually transmitted infections such as human immunodeficiency virus.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: Effector T cells are recruited to the vagina by topical chemokine treatment.
Figure 2: Chemokine pull is specific for highly activated effector T cells.
Figure 3: Virus-specific T cells recruited by chemokine pull are retained in the vagina long term.
Figure 4: Prime and pull protects mice from lethal genital HSV-2 challenge.

References

  1. 1

    McElrath, M. J. & Haynes, B. F. Induction of immunity to human immunodeficiency virus type-1 by vaccination. Immunity 33, 542–554 (2010)

    CAS  Article  Google Scholar 

  2. 2

    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)

    CAS  Article  Google Scholar 

  3. 3

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

    ADS  CAS  Article  Google Scholar 

  4. 4

    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)

    ADS  CAS  Article  Google Scholar 

  5. 5

    Koelle, D. M. & Corey, L. Herpes simplex: insights on pathogenesis and possible vaccines. Annu. Rev. Med. 59, 381–395 (2008)

    CAS  Article  Google Scholar 

  6. 6

    Woodland, D. L. & Kohlmeier, J. E. Migration, maintenance and recall of memory T cells in peripheral tissues. Nature Rev. Immunol. 9, 153–161 (2009)

    CAS  Article  Google Scholar 

  7. 7

    Masopust, D. et al. Dynamic T cell migration program provides resident memory within intestinal epithelium. J. Exp. Med. 207, 553–564 (2010)

    CAS  Article  Google Scholar 

  8. 8

    Klonowski, K. D. et al. Dynamics of blood-borne CD8 memory T cell migration in vivo. Immunity 20, 551–562 (2004)

    CAS  Article  Google Scholar 

  9. 9

    Groom, J. R. & Luster, A. D. CXCR3 ligands: redundant, collaborative and antagonistic functions. Immunol. Cell Biol. 89, 207–215 (2011)

    CAS  Article  Google Scholar 

  10. 10

    Mueller, S. N., Heath, W., McLain, J. D., Carbone, F. R. & Jones, C. M. Characterization of two TCR transgenic mouse lines specific for herpes simplex virus. Immunol. Cell Biol. 80, 156–163 (2002)

    CAS  Article  Google Scholar 

  11. 11

    Jones, C. A., Taylor, T. J. & Knipe, D. M. Biological properties of herpes simplex virus 2 replication-defective mutant strains in a murine nasal infection model. Virology 278, 137–150 (2000)

    CAS  Article  Google Scholar 

  12. 12

    Smith, C. M. et al. Cognate CD4+ T cell licensing of dendritic cells in CD8+ T cell immunity. Nature Immunol. 5, 1143–1148 (2004)

    CAS  Article  Google Scholar 

  13. 13

    Kaech, S. M. & Wherry, E. J. Heterogeneity and cell-fate decisions in effector and memory CD8+ T cell differentiation during viral infection. Immunity 27, 393–405 (2007)

    CAS  Article  Google Scholar 

  14. 14

    Weninger, W., Crowley, M. A., Manjunath, N. & von Andrian, U. H. Migratory properties of naive, effector, and memory CD8+ T cells. J. Exp. Med. 194, 953–966 (2001)

    CAS  Article  Google Scholar 

  15. 15

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

    ADS  CAS  Article  Google Scholar 

  16. 16

    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)

    CAS  Article  Google Scholar 

  17. 17

    Iijima, N. et al. Dendritic cells and B cells maximize mucosal Th1 memory response to herpes simplex virus. J. Exp. Med. 205, 3041–3052 (2008)

    CAS  Article  Google Scholar 

  18. 18

    Parr, M. B. & Parr, E. L. Intravaginal administration of herpes simplex virus type 2 to mice leads to infection of several neural and extraneural sites. J. Neurovirol. 9, 594–602 (2003)

    Article  Google Scholar 

  19. 19

    Mackay, L. K. et al. Long-lived epithelial immunity by tissue-resident memory T (TRM) cells in the absence of persisting local antigen presentation. Proc. Natl Acad. Sci. USA 109, 7037–7042 (2012)

    ADS  CAS  Article  Google Scholar 

  20. 20

    Khanna, K. M., Lepisto, A. J. & Hendricks, R. L. Immunity to latent viral infection: many skirmishes but few fatalities. Trends Immunol. 25, 230–234 (2004)

    CAS  Article  Google Scholar 

  21. 21

    Perkins, N., Nisbet, M. & Thomas, M. Topical imiquimod treatment of aciclovir-resistant herpes simplex disease: case series and literature review. Sex. Transm. Infect. 87, 292–295 (2011)

    Article  Google Scholar 

  22. 22

    Gill, N., Davies, E. J. & Ashkar, A. A. The role of Toll-like receptor ligands/agonists in protection against genital HSV-2 infection. Am. J. Reprod. Immunol. 59, 35–43 (2008)

    CAS  Article  Google Scholar 

  23. 23

    Iwasaki, A. Antiviral immune responses in the genital tract: clues for vaccines. Nature Rev. Immunol. 10, 699–711 (2010)

    CAS  Article  Google Scholar 

  24. 24

    Gajewski, T. F., Fuertes, M., Spaapen, R., Zheng, Y. & Kline, J. Molecular profiling to identify relevant immune resistance mechanisms in the tumor microenvironment. Curr. Opin. Immunol. 23, 286–292 (2011)

    CAS  Article  Google Scholar 

  25. 25

    Parr, M. B. et al. A mouse model for studies of mucosal immunity to vaginal infection by herpes simplex virus type 2. Lab. Invest. 70, 369–380 (1994)

    CAS  PubMed  Google Scholar 

  26. 26

    Spang, A. E., Godowski, P. J. & Knipe, D. M. Characterization of herpes simplex virus 2 temperature-sensitive mutants whose lesions map in or near the coding sequences for the major DNA-binding protein. J. Virol. 45, 332–342 (1983)

    CAS  Article  Google Scholar 

  27. 27

    Malin, S. A., Davis, B. M. & Molliver, D. C. Production of dissociated sensory neuron cultures and considerations for their use in studying neuronal function and plasticity. Nature Protocols 2, 152–160 (2007)

    CAS  Article  Google Scholar 

  28. 28

    Morrison, L. A., Da Costa, X. J. & Knipe, D. M. Influence of mucosal and parenteral immunization with a replication-defective mutant of HSV-2 on immune responses and protection from genital challenge. Virology 243, 178–187 (1998)

    CAS  Article  Google Scholar 

  29. 29

    Aljanabi, S. M. & Martinez, I. Universal and rapid salt-extraction of high quality genomic DNA for PCR-based techniques. Nucleic Acids Res. 25, 4692–4693 (1997)

    CAS  Article  Google Scholar 

  30. 30

    Soderberg, K. A., Linehan, M. M., Ruddle, N. H. & Iwasaki, A. MAdCAM-1 expressing sacral lymph node in the lymphotoxin β-deficient mouse provides a site for immune generation following vaginal herpes simplex virus-2 infection. J. Immunol. 173, 1908–1913 (2004)

    CAS  Article  Google Scholar 

Download references

Acknowledgements

We thank E. Foxman and R. Medzhitov for critical reading of the manuscript, and N. Iijima, H. Dong and B. Yordy for technical support. H.S. is supported by NIAID grant F32AI091024. This work is supported by NIH grants AI054359 and AI062428 to A.I.

Author information

Affiliations

Authors

Contributions

Experiments were conceived and designed by H.S. and A.I. Experiments were performed by H.S. Data were analysed by H.S. and A.I. The paper was written by H.S. and A.I.

Corresponding author

Correspondence to Akiko Iwasaki.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Information

This file contains Supplementary Figures 1-7 and Supplementary Text. (PDF 329 kb)

PowerPoint slides

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Shin, H., Iwasaki, A. A vaccine strategy that protects against genital herpes by establishing local memory T cells. Nature 491, 463–467 (2012). https://doi.org/10.1038/nature11522

Download citation

Further reading

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing