CD40 LIGAND (CD154) STIMULATION OF MACROPHAGES TO PRODUCE HIV-1-SUPPRESSIVE BETA-CHEMOKINES

beta-chemokines play an important role in the development of immunolog ic reactions. Macrophages are major beta-chemokine-producing cells dur ing T-cell directed, delayed-type hypersensitivity reactions in tissue s, and have been reported to be important producers of beta-chemokines in the lymph nodes of HIV-1-infected individuals. However, the physio logical signals responsible for inducing macrophages to produce beta-c hemokines have not been established. Two soluble T cell products, inte rferon-gamma and granulocyte-macrophage colony stimulating factor, wer e added to cultured macro phages, but failed to stimulate the producti on of macrophage inflammatory protein-1 alpha and -1 beta; regulated u pon activation, normal T cell expressed and secreted (RANTES); or mono cyte chemoattractant protein-1. Instead, direct cell-cell contact betw een macrophages and cells engineered to express CD40L (also known as C D154) resulted in the production of large amounts of macrophage inflam matory protein-1 alpha and -1 beta, and RANTES (all ligands for CCR5), and monocyte chemoattractant protein-1 (a ligand for CCR2), Supernata nts from CD40L-stimulated macrophages protected CD4(+) T cells from in fection by a nonsyncytium-inducing strain of HIV-1 (which uses CCR5 as a coreceptor). These results have implications for granulomatous dise ases, and conditions such as atherosclerosis and multiple sclerosis, w here CD40L-bearing cells have been found in the macrophage-rich lesion s where beta-chemokines are being produced. Overall, these findings de fine 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.