Studies on natural, antibody-dependent, and interleukin-2-activated killer-cell activity of a patient with mucolipidosis III as a test of the mannose-6-phosphate lytic acceptor hypothesis.

The natural (NK), antibody-dependent (K), and interleukin-2-generated (LAK) killer-cell activity of a patient with mucolipidosis III (ML III; an autosomal recessive defect in UDP-N-acetylglucosamine: lysosomal enzyme N-acetylglucosamine-1-phosphotransferase) was studied to determine whether or not the defect in the phosphorylation of lysosomal enzyme mannose residues resulted in a failure of target-cell lysis, as would be predicted from recent studies showing NK inhibition by phosphorylated sugars, especially mannose-6-phosphate. The patient was studied in parallel with normal donors known to be at the high and low extremes of NK activity. The following results were obtained: NK activity was markedly elevated against K562, Molt-4, human fibroblasts, HL-60, and MeWo to levels approximately one to two times that of our previous highest donor and five times the mean of normal donors previously tested. Interleukin-2-generated killer-cell activity and antibody-dependent cell-mediated cytotoxicity against antibody-coated P815 cells were normal and increased, respectively. HNK-1-positive cells were normal in frequency (7.3 +/- 1.7%), while lytic conjugates were proportional to activity (3.9 +/- 0.6 vs 2.7 +/- 0.4% for the "high" donor), and this was attributable to an increased proportion of lytic cells. The addition of fresh serum from the ML III patient had no effect on the NK activity of normal donors and the effects of preincubation with interferon (enhancement), monensin (inhibition), fructose-6-phosphate (inhibition), and mannose-6-phosphate (inhibition) were identical to those seen using lymphocytes from normal donors. Studies on the NK activity of the parents and two normal female siblings showed that the father's NK activity was high, the mother's was low, and both siblings' was intermediate but low. The data obtained suggest that the inability of lymphocytes to phosphorylate lysosomal enzyme mannose residues had no effect on NK-, K-, or LAK-cell function and that the mechanism of target-cell lysis is independent of either a mannose-6-phosphate-bearing lytic moiety or a mannose-6-phosphate-dependent ligand mechanism.