IntroductionInterleukin-16 (IL-16; for review, see Cruikshank et al 1 ) is a pleiotropic proinflammatory cytokine that is a potent chemotactic factor for T cells, mast cells (MCs), eosinophils, monocytes, and dendritic cells. [2][3][4][5][6][7] In addition to its chemotactic activity, IL-16 induces T cells to increase their surface expression of the IL-2 receptor and MHC class II protein, as well as their intracellular levels of Ca 2ϩ and inositol-1,4,5-trisphosphate (IP3). 8,9 IL-16 induces eosinophils to generate and release substantial amounts of RANTES, eotaxin, IL-4, and leukotriene C 4 . 10 The cytokine promotes the differentiation and granule maturation of MCs by enhancing the kit ligand (KitL)/stem cell factor-mediated expression of tryptase and chymase. 4 IL-16 also inhibits the HIV-1 infection of T cells, monocytes, dendritic cells, and MCs. 4,[11][12][13][14][15] IL-16 is translated as a 631-residue precursor protein 16,17 that undergoes caspase 3-dependent processing 18 inside cells to yield an N-terminal fragment that translocates to the nucleus to induce G 0 /G 1 cell-cycle arrest in the IL-16-expressing cell. 19 The resulting C-terminal 121-residue fragment that is exocytosed possesses chemotactic activity. IL-16 was the first described T-cell chemoattractant. Despite the fact that the size of its biologically active C-terminal domain is comparable with that of many chemotactic factors, IL-16 lacks the conserved Cys residues found in the CC and CXC families of chemokines. T cells are responsive to many chemokines. Nevertheless, due to its poor degree of amino acid sequence identity with varied CC and CXC chemokines, IL-16 does not exert its biologic effects via a known chemokine receptor such as CCR3, which is expressed on the surfaces of T cells and MCs.Studies have been carried out to identify the surface proteins that participate in IL-16-dependent signaling pathways in immune cells. In this regard, it has been noted that increased IL-16 expression in tissues often is correlated with the presence of large numbers of extravasated CD4 ϩ cells. 20,21 The ability of IL-16 to induce an effective chemotactic response in monocytes often is correlated with the amount of CD4 present on the cell's surface, and the chemotactic response of CD4 ϩ T cells and monocytes to IL-16 is diminished when both populations of cells are exposed to Fab fragments of the anti-CD4 monoclonal antibody (mAb) OKT4. 6 The ability of IL-16 to activate eosinophils also is diminished if these granulocytes are pre-exposed to the OKT4 mAb or to a recombinant, soluble form of CD4. 10 Despite the perceived importance of CD4 in IL-16-mediated signaling of T MCs, monocytes, macrophages, and dendritic cells originate from a common CD34 ϩ myeloid progenitor in the bone marrow. We recently noted that IL-16 is a potent chemotactic factor for in vitro-differentiated human MCs, and that this chemotactic response is associated with Ca 2ϩ mobilization. 4 The observation that the IL-16-mediated chemotaxis of these nontransformed cells could be ...