MECHANISMS BY WHICH HLA-CLASS-II MOLECULES PROTECT HUMAN B LYMPHOID TUMOR-CELLS AGAINST NK-MEDIATED AND LAK-MEDIATED CYTOLYSIS

We have previously shown that mutant B lymphoblastoid cell lines, tota lly deficient in expression of human leucocyte antigen (HLA)-class II molecules, but with normal HLA-class I expression, develop enhanced su sceptibility to natural killer (NK) and lymphokine-activated killer (L AK) cell lysis. The current investigations were aimed at examining the role of HLA-DR and native peptides occupying the antigen-presenting g rooves of HLA-class II molecules in protecting mutants of the same B-l ymphoid lines against LAK-mediated lysis. No augmentation in LAK lysis was observed despite using two mutant B-cell lines (9.22.3 and 3.1.0) that lacked HLA-DR. Both these lines expressed HLA-DP and HLA-DQ. How ever, when using other B-cell lines with point mutations in certain re gions of the HLA-DR alpha-chain (78, 80 and 96) significantly increase d their susceptibility to LAK lysis despite normal expression of HLA-D R and the other class I and II molecules. Of particular interest was t he finding that absence of native peptides in antigen-presenting groov es of all the HLA-class II molecules did not render the mutant B cell (9.5.3) susceptible to LAK lysis. These observations support the conce pt that there are different NK or LAK clones. Certain LAK clones recog nize 'self' major histocompatibility complex (MHC) antigens (but not t he native peptides in their antigen-presenting grooves). Presence of ' self' MHC antigens inhibits such clones. Conversely, other NK or LAK c lones recognize 'non-self' in the context of MHC antigens. Hence, poin t mutations at certain specific sites on the MHC molecules or foreign peptides in the antigen-presenting grooves enhances the susceptibility of these cells to LAK clones recognizing 'non-self'.