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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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.
Reprints and permissions information is available at npg.nature.com/reprintsandpermissions. The authors declare no competing financial interests.
Contains Supplementary Methods; Supplementary Figure legends 1-7; Supplementary Table 1 legend; Supplementary Movie information. (DOC 102 kb)
Contains Supplementary Figures 1-7; Supplementary Table 1. (PPT 1866 kb)
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)
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)
The same movie as in 2a, edited to illustrate T cell movement and contact with DC. (MOV 9931 kb)
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)
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)
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)
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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