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

Nature volume 440, pages 890–895 (2006)Cite this article

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.

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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.

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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

Author notes

  1. Flora Castellino

    Present address: Chiron Vaccines, Via Fiorentina 1, Siena, 53100, Italy

  2. Grégoire Altan-Bonnet

    Present address: cBio, Memorial Sloan-Kettering Cancer Center, New York, New York, 10021, USA

  3. Sabine Stoll

    Present address: Department of Dermatology, University of Mainz, Mainz, 55131, Germany

  4. Clemens Scheinecker

    Present address: Department of Rheumatology, Internal Medicine III, Medical University of Vienna, General Hospital of Vienna, Währinger Gürtel 18-20, A-1090, Vienna, Austria

  5. Flora Castellino and Alex Y. Huang: *These authors contributed equally to this work

Authors and Affiliations

  1. Lymphocyte Biology Section, Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, 20892, USA

    Flora Castellino, Alex Y. Huang, Grégoire Altan-Bonnet, Sabine Stoll, Clemens Scheinecker & Ronald N. Germain

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Correspondence to Ronald N. Germain.

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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)

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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

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