CD8+ T lymphocyte mobilization to virus-infected tissue requires CD4+ T-cell help

Abstract

CD4+ T helper cells are well known for their role in providing critical signals during priming of cytotoxic CD8+ T lymphocyte (CTL) responses in vivo. T-cell help is required for the generation of primary CTL responses as well as in promoting protective CD8+ memory T-cell development1. However, the role of CD4 help in the control of CTL responses at the effector stage is unknown. Here we show that fully helped effector CTLs are themselves not self-sufficient for entry into the infected tissue, but rely on the CD4+ T cells to provide the necessary cue. CD4+ T helper cells control the migration of CTL indirectly through the secretion of IFN-γ and induction of local chemokine secretion in the infected tissue. Our results reveal a previously unappreciated role of CD4 help in mobilizing effector CTL to the peripheral sites of infection where they help to eliminate infected cells.

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: CD4 help is required for CTL migration into the vaginal mucosa after HSV-2 infection.
Figure 2: CD4 T cell-secreted IFN-γ mediates CTL entry into infected vaginal tissue.
Figure 3: CTL recruitment to the infected tissue depends on CXCR3.
Figure 4: Secretion of CTL-recruiting chemokines in the infected tissue depends on CD4 T-cell help.

References

  1. 1

    Williams, M. A. & Bevan, M. J. Effector and memory CTL differentiation. Annu. Rev. Immunol. 25, 171–192 (2007)

    CAS  Article  Google Scholar 

  2. 2

    Bennett, S. R. et al. Help for cytotoxic-T-cell responses is mediated by CD40 signalling. Nature 393, 478–480 (1998)

    ADS  CAS  Article  Google Scholar 

  3. 3

    Ridge, J. P., Di Rosa, F. & Matzinger, P. A conditioned dendritic cell can be a temporal bridge between a CD4+ T-helper and a T-killer cell. Nature 393, 474–478 (1998)

    ADS  CAS  Article  Google Scholar 

  4. 4

    Schoenberger, S. P., Toes, R. E., van der Voort, E. I., Offringa, R. & Melief, C. J. T-cell help for cytotoxic T lymphocytes is mediated by CD40–CD40L interactions. Nature 393, 480–483 (1998)

    ADS  CAS  Article  Google Scholar 

  5. 5

    Jennings, S. R., Bonneau, R. H., Smith, P. M., Wolcott, R. M. & Chervenak, R. CD4-positive T lymphocytes are required for the generation of the primary but not the secondary CD8-positive cytolytic T lymphocyte response to herpes simplex virus in C57BL/6 mice. Cell. Immunol. 133, 234–252 (1991)

    CAS  Article  Google Scholar 

  6. 6

    Janssen, E. M. et al. CD4+ T cells are required for secondary expansion and memory in CD8+ T lymphocytes. Nature 421, 852–856 (2003)

    ADS  CAS  Article  Google Scholar 

  7. 7

    Shedlock, D. J. & Shen, H. Requirement for CD4 T cell help in generating functional CD8 T cell memory. Science 300, 337–339 (2003)

    ADS  CAS  Article  Google Scholar 

  8. 8

    Sun, J. C. & Bevan, M. J. Defective CD8 T cell memory following acute infection without CD4 T cell help. Science 300, 339–342 (2003)

    ADS  CAS  Article  Google Scholar 

  9. 9

    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 

  10. 10

    Zhao, X. et al. Vaginal submucosal dendritic cells, but not Langerhans cells, induce protective Th1 responses to herpes simplex virus-2. J. Exp. Med. 197, 153–162 (2003)

    CAS  Article  Google Scholar 

  11. 11

    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 

  12. 12

    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 

  13. 13

    Stock, A. T. et al. Optimization of TCR transgenic T cells for in vivo tracking of immune responses. Immunol. Cell Biol. 85, 394–396 (2007)

    CAS  Article  Google Scholar 

  14. 14

    Marshall, D. R. et al. Measuring the diaspora for virus-specific CD8+ T cells. Proc. Natl Acad. Sci. USA 98, 6313–6318 (2001)

    ADS  CAS  Article  Google Scholar 

  15. 15

    Masopust, D., Vezys, V., Marzo, A. L. & Lefrancois, L. Preferential localization of effector memory cells in nonlymphoid tissue. Science 291, 2413–2417 (2001)

    ADS  CAS  Article  Google Scholar 

  16. 16

    Lund, J. M., Hsing, L., Pham, T. T. & Rudensky, A. Y. Coordination of early protective immunity to viral infection by regulatory T cells. Science 320, 1220–1224 (2008)

    ADS  CAS  Article  Google Scholar 

  17. 17

    Reboldi, A. et al. C–C chemokine receptor 6-regulated entry of TH-17 cells into the CNS through the choroid plexus is required for the initiation of EAE. Nature Immunol. 10, 514–523 (2009)

    CAS  Article  Google Scholar 

  18. 18

    Milligan, G. N. & Bernstein, D. I. Interferon-γ enhances resolution of herpes simplex virus type 2 infection of the murine genital tract. Virology 229, 259–268 (1997)

    CAS  Article  Google Scholar 

  19. 19

    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 

  20. 20

    Thapa, M., Welner, R. S., Pelayo, R. & Carr, D. J. CXCL9 and CXCL10 expression are critical for control of genital herpes simplex virus type 2 infection through mobilization of HSV-specific CTL and NK cells to the nervous system. J. Immunol. 180, 1098–1106 (2008)

    CAS  Article  Google Scholar 

  21. 21

    Iijima, N., Linehan, M. M., Saeland, S. & Iwasaki, A. Vaginal epithelial dendritic cells renew from bone marrow precursors. Proc. Natl Acad. Sci. USA 104, 19061–19066 (2007)

    ADS  Article  Google Scholar 

  22. 22

    Hancock, W. W. et al. Requirement of the chemokine receptor CXCR3 for acute allograft rejection. J. Exp. Med. 192, 1515–1520 (2000)

    CAS  Article  Google Scholar 

  23. 23

    Sato, A. & Iwasaki, A. Induction of antiviral immunity requires Toll-like receptor signaling in both stromal and dendritic cell compartments. Proc. Natl Acad. Sci. USA 101, 16274–16279 (2004)

    ADS  CAS  Article  Google Scholar 

  24. 24

    Fontenot, J. D. et al. Regulatory T cell lineage specification by the forkhead transcription factor Foxp3. Immunity 22, 329–341 (2005)

    CAS  Article  Google Scholar 

  25. 25

    Iwasaki, A. & Kelsall, B. L. Localization of distinct Peyer’s patch dendritic cell subsets and their recruitment by chemokines macrophage inflammatory protein (MIP)-3α, MIP-3β, and secondary lymphoid organ chemokine. J. Exp. Med. 191, 1381–1394 (2000)

    CAS  Article  Google Scholar 

Download references

Acknowledgements

We thank F. R. Carbone and W. R. Heath for the gBT-I transgenic mouse, A. Rudensky for the foxp3 knock-in mouse, R. Medzhitov and J. M. Thompson for critical reading of the manuscript, and N. Iijima for technical assistance. This work is supported by NIH grants to A.I. (AI054359 and AI062428) and to C.G. (AI39759 and HL51366). Y.N. was a Japan Society for the Promotion of Science fellow. A.I. is a recipient of the Burroughs Wellcome Investigators in Pathogenesis of Infectious Disease.

Author Contributions Experiments were conceived and designed by Y.N. and A.I. Experiments were performed by Y.N. Data were analysed by Y.N. and A.I. The paper was written by Y.N. and A.I. C.G. and B.L. provided CXCR3-knockout mice and discussed the manuscript.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Akiko Iwasaki.

Supplementary information

Supplementary Figures

This file contains Supplementary Figures 1-13 with Legends. (PDF 3307 kb)

PowerPoint slides

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Nakanishi, Y., Lu, B., Gerard, C. et al. CD8+ T lymphocyte mobilization to virus-infected tissue requires CD4+ T-cell help. Nature 462, 510–513 (2009). https://doi.org/10.1038/nature08511

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

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