The gp200-MR6 molecule which is functionally associated with the IL-4 receptor modulates B cell phenotype and is a novel member of the human macrophage mannose receptor family

The human gp200-MR6 molecule has previously been shown to have either an an tagonistic or agonistic effect on IL-4 function, demonstrated by inhibition of IL-4-induced proliferation of T cells or mimicking of IL-4-induced matu ration of epithelium, respectively. We now show that gp200-MR6 ligation can also mimic IL-4 and have an anti-proliferative pro-maturational influence within the immune system, causing up-regulation of co-stimulatory molecules on B lymphocytes. Biochemical analysis and cDNA cloning reveal that gp200- MR6 belongs to the human macrophage mannose receptor family of multidomain molecules. it comprises 1722 amino acids in tote (mature protein, 1695 amin o acids; signal sequence, 27 amino acids) organized into 12 external domain s (an N-terminal cysteine-rich domain, a fibronectin type II domain and 10 C-type carbohydrate recognition domains), a transmembrane region and a smal l cytoplasmic C terminus (31 amino acids) containing a single tyrosine resi due (Y1679), but no obvious kinase domain. Strong amino acid sequence ident ity (77 %) suggests that gp200-MR6 is the human homologue of the murine DEC -205, indicating that this molecule has much wider functional activity than its classical endocytic role. We also show that the gp200-MR6 molecule is closely associated with tyrosine kinase activity; the link between gp200-MR 6 and the IL-4 receptor may therefore be via intracellular signaling pathwa ys, with multifunctionality residing in its extracellular multidomain struc ture.