Chemokines enhance immunity by guiding naive CD8+ T cells to sites of CD4+ T cell-dendritic cell interaction.
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-1alpha and MIP-1beta) 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.
Castellino
Flora
F
Lymphocyte Biology Section, Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
Huang
Alex Y
AY
Altan-Bonnet
Grégoire
G
Stoll
Sabine
S
Scheinecker
Clemens
C
Germain
Ronald N
RN
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology* / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology* / Q000276:immunology; D002448:Cell Adhesion; D002450:Cell Communication; D002465:Cell Movement; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D018925:Chemokines / Q000037:antagonists & inhibitors / Q000276:immunology* / Q000378:metabolism; D019742:Chemokines, CC / Q000276:immunology / Q000378:metabolism; D003713:Dendritic Cells / Q000166:cytology* / Q000276:immunology; D007156:Immunologic Memory / Q000276:immunology; D008198:Lymph Nodes / Q000166:cytology / Q000276:immunology; D008213:Lymphocyte Activation; D019402:Macrophage Inflammatory Proteins / Q000276:immunology / Q000378:metabolism; D051379:Mice; D019713:Receptors, CCR5 / Q000276:immunology / Q000378:metabolism
C496534:Ccl3 protein, mouse; C496535:Ccl4 protein, mouse; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D018925:Chemokines; D019742:Chemokines, CC; D019402:Macrophage Inflammatory Proteins; D019713:Receptors, CCR5