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.

  • Article
  • Published:

Cognate CD4+ T cell licensing of dendritic cells in CD8+ T cell immunity

Nature Immunology volume 5, pages 1143–1148 (2004)Cite this article

Abstract

Several studies have indicated that CD8+ T cells require CD4+ T cell help for memory formation. Evidence suggests that such help can be antigen independent, challenging whether the 'licensing' of dendritic cells (DCs) by CD4+ T cells is ever required for cytotoxic T lymphocyte (CTL) responses. We show here that help is essential for the generation of CTL immunity to herpes simplex virus 1 and that CD4+ T cells mediate help in a cognate, antigen-specific way. We provide direct in vivo evidence for DC licensing by helper T cells and show that licensing is rapid and essential for the formation of effector and memory CTLs. In situations in which DCs are poorly licensed by pathogen-derived signals, our findings suggest that CTL immunity may be heavily dependent on cognate DC licensing.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Generation of CD8+ T cell immunity to HSV-1 after subcutaneous infection requires cognate CD4+ T cell help.
Figure 2: Generation of CD8+ T cell immunity to HSV-1 after intravenous infection requires cognate CD4+ T cell help.
Figure 3: CD8+ DCs are licensed by helpers and promote the generation of memory phenotype CD8+ T cells.
Figure 4: CD8+ DCs from B6 mice but not MHC class II–deficient mice are licensed following viral infection.
Figure 5: Cognate recognition of antigen by helper T cells is required for licensing of CD8+ DCs.
Figure 6: CD8+ DCs are licensed by 26 h after infection.
Figure 7: Licensed CD8+ DCs stimulate efficient CTL memory.

Similar content being viewed by others

References

  1. Bevan, M.J. Helping the CD8+ T-cell response. Nat. Rev. Immunol. 4, 595–602 (2004).

    Article  CAS  Google Scholar 

  2. Bourgeois, C., Rocha, B. & Tanchot, C. A role for CD40 expression on CD8+ T cells in the generation of CD8+ T cell memory. Science 297, 2060–2063 (2002).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  6. Sun, J.C., Williams, M.A. & Bevan, M.J. CD4+ T cells are required for the maintenance, not programming, of memory CD8+ T cells after acute infection. Nat. Immunol. 5, 927–933 (2004).

    Article  CAS  Google Scholar 

  7. 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).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  9. Bennett, S.R., Carbone, F.R., Karamalis, F., Miller, J.F. & Heath, W.R. Induction of a CD8+ cytotoxic T lymphocyte response by cross-priming requires cognate CD4+ T cell help. J. Exp. Med. 186, 65–70 (1997).

    Article  CAS  Google Scholar 

  10. Marzo, A.L. et al. Fully functional memory CD8 T cells in the absence of CD4 T cells. J. Immunol. 173, 969–975 (2004).

    Article  CAS  Google Scholar 

  11. Husmann, L.A. & Bevan, M.J. Cooperation between helper T cells and cytotoxic T lymphocyte precursors. Ann. NY Acad. Sci. 532, 158–169 (1988).

    Article  CAS  Google Scholar 

  12. Guerder, S. & Matzinger, P. A fail-safe mechanism for maintaining self-tolerance. J. Exp. Med. 176, 553–564 (1992).

    Article  CAS  Google Scholar 

  13. Krieger, N.R., Yin, D.P. & Garrison Fathman, C. CD4+ but not CD8+ cells are essential for allorejection. J. Exp. Med. 184, 2013–2018 (1996).

    Article  CAS  Google Scholar 

  14. 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).

    Article  CAS  Google Scholar 

  15. Cassell, D. & Forman, J. Linked recognition of helper and cytotoxic antigenic determinants for the generation of cytotoxic T lymphocytes. Ann. NY Acad. Sci. 532, 51–60 (1988).

    Article  CAS  Google Scholar 

  16. Mitchison, N.A. & O'Malley, C. Three-cell-type clusters of T cells with antigen-presenting cells best explain the epitope linkage and noncognate requirements of the in vivo cytolytic response. Eur. J. Immunol. 17, 1579–1583 (1987).

    Article  CAS  Google Scholar 

  17. 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).

    Article  CAS  Google Scholar 

  18. Schuurhuis, D.H. et al. Immature dendritic cells acquire CD8+ cytotoxic T lymphocyte priming capacity upon activation by T helper cell-independent or -dependent stimuli. J. Exp. Med. 192, 145–150 (2000).

    Article  CAS  Google Scholar 

  19. Belz, G.T., Wodarz, D., Diaz, G., Nowak, M.A. & Doherty, P.C. Compromised influenza virus-specific CD8+-T-cell memory in CD4+-T-cell-deficient mice. J. Virol. 76, 12388–12393 (2002).

    Article  CAS  Google Scholar 

  20. Sun, J.C. & Bevan, M.J. Cutting edge: long-lived CD8 memory and protective immunity in the absence of CD40 expression on CD8 T cells. J. Immunol. 172, 3385–3389 (2004).

    Article  CAS  Google Scholar 

  21. Le Bon, A. et al. Cross-priming of CD8+ T cells stimulated by virus-induced type I interferon. Nat. Immunol. 4, 1009–1015 (2003).

    Article  CAS  Google Scholar 

  22. Wang, J.C. & Livingstone, A.M. Cutting edge: CD4+ T cell help can be essential for primary CD8+ T cell responses in vivo. J. Immunol. 171, 6339–6343 (2003).

    Article  CAS  Google Scholar 

  23. Behrens, G.M. et al. Helper requirements for generation of effector CTL to islet beta cell antigens. J. Immunol. 172, 5420–5426 (2004).

    Article  CAS  Google Scholar 

  24. Allan, R.S. et al. Epidermal viral immunity induced by CD8α+ dendritic cells but not by Langerhans cells. Science 301, 1925–1928 (2003).

    Article  CAS  Google Scholar 

  25. Heath, W.R. et al. Cross-presentation, dendritic cell subsets, and the generation of immunity to cellular antigens. Immunol. Rev. 199, 9–26 (2004).

    Article  CAS  Google Scholar 

  26. Smith, C.M. et al. Cutting edge: Conventional CD8α+ dendritic cells are preferentially involved in CTL priming after footpad infection with herpes simplex virus-1. J. Immunol. 170, 4437–4440 (2003).

    Article  CAS  Google Scholar 

  27. Belz, G.T. et al. Cutting edge: Conventional CD8α+ dendritic cells are generally involved in priming CTL immunity to viruses. J. Immunol. 172, 1996–2000 (2004).

    Article  CAS  Google Scholar 

  28. Kaech, S.M. et al. Selective expression of the interleukin 7 receptor identifies effector CD8 T cells that give rise to long-lived memory cells. Nat. Immunol. 4, 1191–1198 (2003).

    Article  CAS  Google Scholar 

  29. Lauvau, G. et al. Priming of memory but not effector CD8 T cells by a killed bacterial vaccine. Science 294, 1735–1739 (2001).

    Article  CAS  Google Scholar 

  30. Ahmed, R., Butler, L.D. & Bhatti, L. T4+ T helper cell function in vivo: differential requirement for induction of antiviral cytotoxic T-cell and antibody responses. J. Virol. 62, 2102–2106 (1988).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Buller, R.M., Holmes, K.L., Hugin, A., Frederickson, T.N. & Morse, H.C.D. Induction of cytotoxic T-cell responses in vivo in the absence of CD4 helper cells. Nature 328, 77–79 (1987).

    Article  CAS  Google Scholar 

  32. Liu, Y. & Mullbacher, A. The generation and activation of memory class I MHC restricted cytotoxic T cell responses to influenza A virus in vivo do not require CD4+ T cells. Immunol. Cell Biol. 67, 413–420 (1989).

    Article  Google Scholar 

  33. Mempel, T.R., Henrickson, S.E. & Von Andrian, U.H. T-cell priming by dendritic cells in lymph nodes occurs in three distinct phases. Nature 427, 154–159 (2004).

    Article  CAS  Google Scholar 

  34. Weiss, E.H. et al. The structure of a mutant H-2 gene suggests that the generation of polymorphism in H-2 genes may occur by gene conversion-like events. Nature 301, 671–674 (1983).

    Article  CAS  Google Scholar 

  35. Gosgrove, D. et al. Mice lacking MHC class II molecules. Cell 66, 1051–1066 (1991).

    Article  Google Scholar 

  36. Hogquist, K.A. et al. T cell receptor antagonist peptides induce positive selection. Cell 76, 17–27 (1994).

    Article  CAS  Google Scholar 

  37. Mueller, S.N., Heath, W.R., Carbone, F.R. & Jones, C.M. The characterisation of two transgenic mice specific for herpes simplex virus. Immunol. Cell Biol. 80, 156–163 (2002).

    Article  CAS  Google Scholar 

  38. Mueller, S.N., Jones, C.M., Smith, C.M., Heath, W.R. & Carbone, F.R. Rapid cytotoxic T lymphocyte activation occurs in the draining lymph nodes after cutaneous herpes simplex virus infection as a result of early antigen presentation and not the presence of virus. J. Exp. Med. 195, 651–656 (2002).

    Article  CAS  Google Scholar 

  39. Jones, C.M. et al. Herpes simplex virus type 1-specific cytotoxic T-lymphocyte arming occurs within lymph nodes draining the site of cutaneous infection. J. Virol. 74, 2414–2419 (2000).

    Article  CAS  Google Scholar 

  40. Sherman, L.A. & Randolph, C.P. Monoclonal anti-H-2Kb antibodies detect serological differences between H-2Kb mutants. Immunogenetics 12, 183–186 (1981).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank K. Shortman and D. Huang for providing antibodies; J.L. Tan, J. Langley, L.M. Kleinert, M. Camilleri and the staff of the Walter and Eliza Hall Institute flow cytometry facility for technical assistance. Supported by the National Health and Medical Research Institute (Australia), Howard Hughes Medical Institute and Wellcome Trust Medical Research Fund (UK).

Author information

Authors and Affiliations

  1. Division of Immunology, Melbourne, 3050, Victoria, Australia

    Christopher M Smith, Nicholas S Wilson, Jose A Villadangos, William R Heath & Gabrielle T Belz

  2. The Co-operative Research Centre for Vaccine Technology at The Walter and Eliza Hall Institute of Medical Research, Melbourne, 3050, Victoria, Australia

    Christopher M Smith, Nicholas S Wilson, Jose A Villadangos, William R Heath & Gabrielle T Belz

  3. Department of Microbiology and Immunology, The University of Melbourne, Melbourne, 3010, Victoria, Australia

    Jason Waithman & Francis R Carbone

Authors
  1. Christopher M Smith
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Nicholas S Wilson
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jason Waithman
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jose A Villadangos
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Francis R Carbone
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. William R Heath
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Gabrielle T Belz
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to William R Heath or Gabrielle T Belz.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

tetramer-positive CD8+ T cell responses to subcutaneous HSV infection requires CD4+ T cell help. (PDF 21 kb)

Supplementary Fig. 2

Efficient gB-specific cytotoxicity to HSV after subcutaneous infection requires CD4+ T cell help. (PDF 103 kb)

Supplementary Fig. 3

CD8 DCs are licensed by 26 h after infection as measured by the ability to stimulate proliferation of OT-I cells. (PDF 115 kb)

Supplementary Fig. 4

CD8 DCs are licensed by 26 h after infection as measured by upregulation of IL-7 receptor on gBT-I cells. (PDF 81 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Smith, C., Wilson, N., Waithman, J. et al. Cognate CD4+ T cell licensing of dendritic cells in CD8+ T cell immunity. Nat Immunol 5, 1143–1148 (2004). https://doi.org/10.1038/ni1129

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ni1129

This article is cited by

Search

Advanced 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