CD40 ligand (CD154) stimulation of macrophages to produce HIV-1-suppressive beta-chemokines.
beta-chemokines play an important role in the development of immunologic reactions. Macrophages are major beta-chemokine-producing cells during T-cell directed, delayed-type hypersensitivity reactions in tissues, and have been reported to be important producers of beta-chemokines in the lymph nodes of HIV-1-infected individuals. However, the physiological signals responsible for inducing macrophages to produce beta-chemokines have not been established. Two soluble T cell products, interferon-gamma and granulocyte-macrophage colony stimulating factor, were added to cultured macrophages, but failed to stimulate the production of macrophage inflammatory protein-1alpha and -1beta; regulated upon activation, normal T cell expressed and secreted (RANTES); or monocyte chemoattractant protein-1. Instead, direct cell-cell contact between macrophages and cells engineered to express CD40L (also known as CD154) resulted in the production of large amounts of macrophage inflammatory protein-1alpha and -1beta, and RANTES (all ligands for CCR5), and monocyte chemoattractant protein-1 (a ligand for CCR2). Supernatants from CD40L-stimulated macrophages protected CD4(+) T cells from infection by a nonsyncytium-inducing strain of HIV-1 (which uses CCR5 as a coreceptor). These results have implications for granulomatous diseases, and conditions such as atherosclerosis and multiple sclerosis, where CD40L-bearing cells have been found in the macrophage-rich lesions where beta-chemokines are being produced. Overall, these findings define a pathway linking the specific recognition of antigen by T cells to the production of beta-chemokines by macrophages. This pathway may play a role in anti-HIV-1 immunity and the development of immunologic reactions or lesions.
Kornbluth
R S
RS
Department of Medicine, University of California, San Diego, and Department of Veterans Affairs Medical Center, La Jolla, CA 92093, USA. rkornbluth@ucsd.edu
Kee
K
K
Richman
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DD
D023201:CD40 Ligand; D002450:Cell Communication; D002462:Cell Membrane / Q000502:physiology; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000096:biosynthesis; D019742:Chemokines, CC / Q000096:biosynthesis*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D015497:HIV-1 / Q000254:growth & development*; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology; D008264:Macrophages / Q000502:physiology*; D008562:Membrane Glycoproteins / Q000502:physiology*; D013601:T-Lymphocytes / Q000276:immunology / Q000821:virology; D014779:Virus Replication
D018932:Chemokine CCL2; D019742:Chemokines, CC; D008562:Membrane Glycoproteins; D023201:CD40 Ligand; D007371:Interferon-gamma; D016178:Granulocyte-Macrophage Colony-Stimulating Factor