SELF CLASS-I MOLECULES PROTECT NORMAL-CELLS FROM LYSIS MEDIATED BY AUTOLOGOUS NATURAL-KILLER-CELLS

The surface expression of given HLA class I alleles protects target ce lls from lysis mediated by natural killer (NK) clones specific for the se (or related) alleles. We could define two groups of NK clones speci fically recognizing either Cw4 and related C alleles (''group 1'') or Cw3 and related C alleles (''group 2''), respectively. Monoclonal anti bodies (mAb) to class I molecules should interfere with the interactio n between NK receptors and class I molecules, thus resulting in lysis of protected target cells. However, none of the numerous available mAb to class I molecules had this effect. Therefore, we attempted to sele ct new mAb on the basis of their ability to induce lysis of Cw4- or Cw 3-protected lymphoblastoid cell lines by ''group 1'' or ''group 2'' NK clones, respectively. From mice immunized with phytohemagglutinin (PH A)-activated lymphocytes expressing either Cw3 or Cw4 alleles, two mAb were selected, the 6A4 (IgG1) and the A6-136 (IgM), on the basis of t heir ability to induce lysis of protected target cell. Both mAb immuno precipitated molecules which, in sodium dodecyl sulfate-polyacrylamide gel electrophoresis, gave two bands of 45 and 12 kDa, typical of the class I heavy chain and beta 2 microglobulin, respectively. It has bee n proposed (but not proven), that self major histocompatibility comple x class I molecules protect normal cells from autologous NK cell lysis . Thus, we used the 6A4 and A6-136 mAb to assess this possibility dire ctly. Cw4-specific (''group 1'') and Cw3-specific (''group 2'') NK clo nes were isolated from donors expressing the corresponding (or related ) protective C alleles. None of these clones lysed autologous PHA-indu ced blasts, used as target cells. However, addition of the F(ab')(2) o f 6A4 mAb or the A6-136 mAb resulted in lysis of autologous target cel ls by ''group 1'' or ''group 2'' NK clones, respectively. These data p rovide direct evidence that the expression of class I molecules protec ts normal cells from lysis by autologous NK cells.