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-1 and MIP-1) 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.

1. Lymphocyte Biology Section, Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA
2. †Present addresses: Chiron Vaccines, Via Fiorentina 1, Siena 53100, Italy (F.C.); cBio, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA (G.A.-B.); Department of Dermatology, University of Mainz, Mainz 55131, Germany (S.S.); Department of Rheumatology, Internal Medicine III, Medical University of Vienna, General Hospital of Vienna, Währinger Gürtel 18-20, A-1090 Vienna, Austria (C.S.)
3. *These authors contributed equally to this work

Correspondence to: Ronald N. Germain¹ Correspondence and requests for materials should be addressed to R.N.G. (Email: rgermain@nih.gov).

Received 22 November 2005 | Accepted 15 February 2006

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