Self class I molecules protect normal cells from lysis mediated by autologous natural killer cells

Abstract

The surface expression of given HLA class I alleles protects target cells from lysis mediated by natural killer (NK) clones specific for these (or related) alleles. We could define two groups of NK clones specifically recognizing either Cw4 and related C alleles ("group 1") or Cw3 and related C alleles ("group 2"), respectively. Monoclonal antibodies (mAb) to class I molecules should interfere with the interaction 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 select new mAb on the basis of their ability to induce lysis of Cw4- or Cw3-protected lymphoblastoid cell lines by "group 1" or "group 2" NK clones, respectively. From mice immunized with phytohemagglutinin (PHA)-activated lymphocytes expressing either Cw3 or Cw4 alleles, two mAb were selected, the 6A4 (IgG1) and the A6-136 (IgM), on the basis of their ability to induce lysis of protected target cell. Both mAb immunoprecipitated 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 been proposed (but not proven), that self major histocompatibility complex class I molecules protect normal cells from autologous NK cell lysis. Thus, we used the 6A4 and A6-136 mAb to assess this possibility directly. Cw4-specific ("group 1") and Cw3-specific ("group 2") NK clones were isolated from donors expressing the corresponding (or related) protective C alleles. None of these clones lysed autologous PHA-induced blasts, used as target cells. However, addition of the F(ab')2 of 6A4 mAb or the A6-136 mAb resulted in lysis of autologous target cells by "group 1" or "group 2" NK clones, respectively. These data provide direct evidence that the expression of class I molecules protects normal cells from lysis by autologous NK cells.

Coexpression of two functionally independent p58 inhibitory receptors in human natural killer cell clones results in the inability to kill all normal allogeneic target cells.

“…Monoclonal antibodies (mAbs) OKT3 (IgG2a anti-CD3; Ortho Pharmaceuticals), JT3A (IgG2a anti-CD3), HP2.6 (IgG2a anti-CD4), B9.4 (IgG2b anti-CD8), GL183 (IgGl anti-p58), EB6 (IgGl anti-p58), (IgM anti-p58), KD1 (IgG2a anti-CD16), K218 (IgGl anti-CD56), A6-220 (IgM anti-CD56), 6A4 (IgGl anti-HLA class I), and A6-136 (IgM anti-HLA class I) (12) were used in this study.…”

Expression of inhibitory KIR is confined to CD8+ effector T cells and limits their proliferative capacity

“…These receptors control NK cell tolerance [1] and allow NK cells to mediate their cytotoxic function towards cells showing an altered MHC class I expression during tumor development [2] or viral infection [3]. In humans, two families of NK cell receptors (NKR) with a different protein structure have been described [4].…”

Human CD8+ T lymphocyte subsets that express HLA class I-specific inhibitory receptors represent oligoclonally or monoclonally expanded cell populations.

“…Different NK-Rs, specific for groups of HLA-C (p58.1 and p58.2), HLA-B (p70 and CD94), or HLA-A (p140) alleles, have been identified (5)(6)(7)(8). In most instances, they function as inhibitory receptors, thus preventing the NK-mediated lysis of cells that express the relevant HLA class I allele(s) (9,10). All NK cells express at least one type of inhibitory NK-R for a given self HLA class I allele (5,11).…”