DEVELOPMENTAL REGULATION OF A MUCIN-LIKE GLYCOPROTEIN SELECTIVELY EXPRESSED ON NATURAL-KILLER-CELLS

Natural killer (NK) cells are CD3:TCR-, CD16+, CD56+ large granular ly mphocytes capable of recognizing and eliminating a variety of virus-in fected, malignant, and antibody-coated target cells. Two functionally distinct populations of peripheral blood NK cells can be differentiate d by their surface expression of an isoform of the neural cell adhesio n molecule (CD56). CD56bright NK cells have the attributes of an undif ferentiated cell, in that they proliferate in response to exogenous cy tokines, but exert poor cytolytic activity. CD56dim NK cells have the attributes of a more differentiated cell, in that they proliferate poo rly in response to exogenous cytokines, but are potent cytolytic effec tor cells. Here we describe the molecular characterization of a NK cel l restricted epitope (PEN5) that is selectively expressed on the funct ionally differentiated CD56dim NK cells. PEN5+ NK cells proliferate po orly in response to interleukin 2 (IL-2), but are potent cytolytic eff ectors, whereas PEN5- NK cells proliferate in response to IL-2, but ar e poor cytolytic effectors. Biochemical and immunochemical analyses re veal the PEN5 epitope to be an unusual sulfated poly-N-lactosamine car bohydrate related to keratan sulfate glycosaminoglycans. Immunoprecipi tates prepared using a monoclonal antibody reactive with PEN5 include two polydisperse membrane-bound glycoproteins, PEN5alpha (120-170 kD) and PEN5beta (210-245 kD). Enzymatic deglycosylation reduces the appar ent molecular weight of both PEN5 isoforms by 80-90%, and classifies P EN5beta as a mucinlike glycoprotein. The surface expression of the PEN 5 epitope is downmodulated by stimuli that induce NK cell proliferatio n, and it is absent from leukemic NK cells of patients with granular l ymphocyte proliferative disorder. Taken together, these results indica te that PEN5 is a developmentally regulated poly-N-lactosamine epitope associated with a mucin-type glycoprotein, whose expression is restri cted to the population of nonproliferative NK cells fully committed to cytolytic effector function.