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.

Chemokines enhance immunity by guiding naive CD8+ T cells to sites of CD4+ T cell–dendritic cell interaction

Abstract

CD8+ T cells have a crucial role in resistance to pathogens and can kill malignant cells; however, some critical functions of these lymphocytes depend on helper activity provided by a distinct population of CD4+ T cells. Cooperation between these lymphocyte subsets involves recognition of antigens co-presented by the same dendritic cell, but the frequencies of such antigen-bearing cells early in an infection and of the relevant naive T cells are both low. This suggests that an active mechanism facilitates the necessary cell–cell associations. Here we demonstrate that after immunization but before antigen recognition, naive CD8+ T cells in immunogen-draining lymph nodes upregulate the chemokine receptor CCR5, permitting these cells to be attracted to sites of antigen-specific dendritic cell–CD4+ T cell interaction where the cognate chemokines CCL3 and CCL4 (also known as MIP-1α and MIP-1β) are produced. Interference with this actively guided recruitment markedly reduces the ability of CD4+ T cells to promote memory CD8+ T-cell generation, indicating that an orchestrated series of differentiation events drives nonrandom cell–cell interactions within lymph nodes, optimizing CD8+ T-cell immune responses involving the few antigen-specific precursors present in the naive repertoire.

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: CD8 + T cells accumulate in lymph nodes in which antigen-dependent CD4 + T cell–dendritic cell interactions are occurring.
Figure 2: Increased frequency of cellular contacts between CD8 + T cells and dendritic cells capable of antigen-dependent interaction with CD4 + T cells.
Figure 3: Role of CCL3 and CCL4 in the CD4 + T cell–dendritic cell-dependent accumulation of CD8 + T cells within lymph nodes draining an immunization site.
Figure 4: Wild-type CD8 + T cells exhibit chemokine-directed rapid jumps and directional migration towards OVA 323–339-pulsed dendritic cells.
Figure 5: Role of CCL3 and CCL4 in CD4 + T help for CD8 + T-cell memory.

References

  1. 1

    Germain, R. N. & Castellino, F. Co-operation between CD4+ and CD8+ T cells: when, where, and how. Annu. Rev. Immunol. (in the press)

  2. 2

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

    CAS  Article  Google Scholar 

  3. 3

    Kaech, S. M., Wherry, E. J. & Ahmed, R. Effector and memory T-cell differentiation: implications for vaccine development. Nature Rev. Immunol. 2, 251–262 (2002)

    CAS  Article  Google Scholar 

  4. 4

    Keene, J. A. & Forman, J. Helper activity is required for the in vivo generation of cytotoxic T lymphocytes. J. Exp. Med. 155, 768–782 (1982)

    CAS  Article  Google Scholar 

  5. 5

    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)

    ADS  CAS  Article  Google Scholar 

  6. 6

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

    CAS  Article  Google Scholar 

  7. 7

    Miller, M. J., Wei, S. H., Parker, I. & Cahalan, M. D. Two-photon imaging of lymphocyte motility and antigen response in intact lymph node. Science 296, 1869–1873 (2002)

    ADS  CAS  Article  Google Scholar 

  8. 8

    Miller, M. J., Wei, S. H., Cahalan, M. D. & Parker, I. Autonomous T cell trafficking examined in vivo with intravital two-photon microscopy. Proc. Natl Acad. Sci. USA 100, 2604–2609 (2003)

    ADS  CAS  Article  Google Scholar 

  9. 9

    Miller, M. J., Hejazi, A. S., Wei, S. H., Cahalan, M. D. & Parker, I. T cell repertoire scanning is promoted by dynamic dendritic cell behavior and random T cell motility in the lymph node. Proc. Natl Acad. Sci. USA 101, 998–1003 (2004)

    ADS  CAS  Article  Google Scholar 

  10. 10

    Bousso, P. & Robey, E. Dynamics of CD8+ T cell priming by dendritic cells in intact lymph nodes. Nature Immunol. 4, 579–585 (2003)

    CAS  Article  Google Scholar 

  11. 11

    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)

    ADS  CAS  Article  Google Scholar 

  12. 12

    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 

  13. 13

    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 

  14. 14

    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 

  15. 15

    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 

  16. 16

    Stoll, S., Delon, J., Brotz, T. M. & Germain, R. N. Dynamic imaging of T cell-dendritic cell interactions in lymph nodes. Science 296, 1873–1876 (2002)

    ADS  Article  Google Scholar 

  17. 17

    Sallusto, F. & Lanzavecchia, A. Understanding dendritic cell and T-lymphocyte traffic through the analysis of chemokine receptor expression. Immunol. Rev. 177, 134–140 (2000)

    CAS  Article  Google Scholar 

  18. 18

    Cyster, J. G. Lymphoid organ development and cell migration. Immunol. Rev. 195, 5–14 (2003)

    CAS  Article  Google Scholar 

  19. 19

    Proietto, A. I. et al. Differential production of inflammatory chemokines by murine dendritic cell subsets. Immunobiology 209, 163–172 (2004)

    CAS  Article  Google Scholar 

  20. 20

    Clarke, S. R. et al. Characterization of the ovalbumin-specific TCR transgenic line OT-I: MHC elements for positive and negative selection. Immunol. Cell Biol. 78, 110–117 (2000)

    CAS  Article  Google Scholar 

  21. 21

    Barnden, M. J., Allison, J., Heath, W. R. & Carbone, F. R. Defective TCR expression in transgenic mice constructed using cDNA-based α- and β-chain genes under the control of heterologous regulatory elements. Immunol. Cell Biol. 76, 34–40 (1998)

    CAS  Article  Google Scholar 

  22. 22

    MartIn-Fontecha, A. et al. Regulation of dendritic cell migration to the draining lymph node: impact on T lymphocyte traffic and priming. J. Exp. Med. 198, 615–621 (2003)

    CAS  Article  Google Scholar 

  23. 23

    Cahill, R. N., Frost, H. & Trnka, Z. The effects of antigen on the migration of recirculating lymphocytes through single lymph nodes. J. Exp. Med. 143, 870–888 (1976)

    CAS  Article  Google Scholar 

  24. 24

    Hall, J. G. & Morris, B. The immediate effect of antigens on the cell output of a lymph node. Br. J. Exp. Pathol. 46, 450–454 (1965)

    CAS  PubMed  PubMed Central  Google Scholar 

  25. 25

    Huang, A. Y., Qi, H. & Germain, R. N. Illuminating the landscape of in vivo immunity: insights from dynamic in situ imaging of secondary lymphoid tissues. Immunity 21, 331–339 (2004)

    CAS  PubMed  Google Scholar 

  26. 26

    Lindquist, R. L. et al. Visualizing dendritic cell networks in vivo. Nature Immunol. 5, 1243–1250 (2004)

    CAS  Article  Google Scholar 

  27. 27

    Nagorsen, D., Marincola, F. M. & Panelli, M. C. Cytokine and chemokine expression profiles of maturing dendritic cells using multiprotein platform arrays. Cytokine 25, 31–35 (2004)

    CAS  Article  Google Scholar 

  28. 28

    Guan, E., Wang, J. & Norcross, M. A. Identification of human macrophage inflammatory proteins 1α and 1β as a native secreted heterodimer. J. Biol. Chem. 276, 12404–12409 (2001)

    CAS  Article  Google Scholar 

  29. 29

    Sherry, B. et al. Resolution of the two components of macrophage inflammatory protein 1, and cloning and characterization of one of those components, macrophage inflammatory protein 1β. J. Exp. Med. 168, 2251–2259 (1988)

    CAS  Article  Google Scholar 

  30. 30

    Witt, C. M., Raychaudhuri, S., Schaefer, B., Chakraborty, A. K. & Robey, E. A. Directed migration of positively selected thymocytes visualized in real time. PLoS Biol. 3, e160 (2005)

    Article  Google Scholar 

  31. 31

    Hommel, M. & Kyewski, B. Dynamic changes during the immune response in T cell-antigen-presenting cell clusters isolated from lymph nodes. J. Exp. Med. 197, 269–280 (2003)

    CAS  Article  Google Scholar 

  32. 32

    Molon, B. et al. T cell costimulation by chemokine receptors. Nature Immunol. 6, 465–471 (2005)

    CAS  Article  Google Scholar 

  33. 33

    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 

  34. 34

    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 

  35. 35

    Banchereau, J. & Steinman, R. M. Dendritic cells and the control of immunity. Nature 392, 245–252 (1998)

    ADS  CAS  Article  Google Scholar 

  36. 36

    Catron, D. M., Itano, A. A., Pape, K. A., Mueller, D. L. & Jenkins, M. K. Visualizing the first 50 hr of the primary immune response to a soluble antigen. Immunity 21, 341–347 (2004)

    CAS  Article  Google Scholar 

  37. 37

    Klinman, D. M. Immunotherapeutic uses of CpG oligodeoxynucleotides. Nature Rev. Immunol. 4, 249–258 (2004)

    CAS  Article  Google Scholar 

  38. 38

    von Andrian, U. H. & Mempel, T. R. Homing and cellular traffic in lymph nodes. Nature Rev. Immunol. 3, 867–878 (2003)

    CAS  Article  Google Scholar 

Download references

Acknowledgements

We thank C. Reis e Sousa and H. Qi for review of the manuscript, and J. Zhu for advice and assistance with the Q-PCR analyses. This work was supported by the Intramural Research Program of the NIH, NIAID. A.Y.H. is supported by a postdoctoral fellowship grant from the Cancer Research Institute.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Ronald N. Germain.

Ethics declarations

Competing interests

Reprints and permissions information is available at npg.nature.com/reprintsandpermissions. The authors declare no competing financial interests.

Supplementary information

Supplementary Data 1

Contains Supplementary Methods; Supplementary Figure legends 1-7; Supplementary Table 1 legend; Supplementary Movie information. (DOC 102 kb)

Supplementary Data 2

Contains Supplementary Figures 1-7; Supplementary Table 1. (PPT 1866 kb)

Supplementary Movie 1

323-pulsed (blue) and unpulsed (yellow) DCs were co-injected s.c. in the dorsum of the foot of a recipient mouse. (MOV 9264 kb)

Supplementary Movie 2a

An enlarged view of S Movie 1 demonstrating the increased frequency of contact between polyclonal CD8+ T cells (green) and 323-pulsed DC (blue) as compared to that between CD8+ T cells and unpulsed DC (yellow) only a few microns away in the same imaging field. (MOV 3255 kb)

Supplementary Movie 2b

The same movie as in 2a, edited to illustrate T cell movement and contact with DC. (MOV 9931 kb)

Supplementary Movie 3

323-pulsed DC (blue) together with OT-II CD4+ T cells (unlabeled), and CCR5-/- (green) and WT (red) polyclonal CD8+ T cells were imaged in the draining LN 75 - 125 µm below the capsule 16 hours after T cell transfer. (MOV 5659 kb)

Supplementary Movie 4a

A selected field from S Movie 3 that illustrates differences in the contact frequency between 323-pulsed (blue) DCs and each of the two polyclonal CD8+ T cell populations. T cell migration near DCs is shown at 450x the actual speed (WT: red, left panel; CCR5-/-: green, right panel). (MOV 5125 kb)

Supplementary Movie 4b

A selected field from S Movie 3 that illustrates differences in the contact frequency between 323-pulsed (blue) DCs and each of the two polyclonal CD8+ T cell populations. 57 contacts are made between 323-bearing DCs and WT CD8+ T cells (red dots and circles, left panel) as compared to 6 contacts between the same DCs and CCR5-/- CD8+ T cells (green dots and circles, right panel), resulting in a calculated hit rate ratio of 3.26 for WT versus CCR5-/- CD8+ T cells interacting with DCs (see also Fig. 3c). (MOV 23963 kb)

Supplementary Movie 5

Dynamic intravital imaging at 40-100 µm below the capsule of a draining LN 20 hours after labelled T cell transfer captures the formation of a ternary cluster involving a 323-pulsed DC (blue), an OT-II CD4+ T cell (red), and a polyclonal CD8+ T cell (green). (MOV 1403 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Castellino, F., Huang, A., Altan-Bonnet, G. et al. Chemokines enhance immunity by guiding naive CD8+ T cells to sites of CD4+ T cell–dendritic cell interaction. Nature 440, 890–895 (2006). https://doi.org/10.1038/nature04651

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