P58 molecules as putative receptors for major histocompatibility complex (MHC) class I molecules in human natural killer (NK) cells. Anti-p58 antibodies reconstitute lysis of MHC class I-protected cells in NK clones displaying different specificities.

Abstract

SummaryHuman CD3-16 + 56 § natural killer (NK) cells have been shown to display a donaUy distributed ability to recognize major histocompatibility complex (MHC) class I alleles. Opposite to T lymphocytes, in NK cells, specific recognition of MHC class I molecttles appears to induce inhibition of cytolytic activity and, thus, to protect target cells. Since a precise correlation has been established between the expression of the NK-specific GL183 and EB6 surface molecules (belonging to the novel p58 molecular family) and the specificity of NK clones, we analyzed whether p58 molecules could function as receptors for MHC in human NK cells. NK clones displaying the previously defined "specificity 2" and characterized by the GL183 + EB6 + phenotype, specifically recognize the Cw3 allele and thus fail to lyse the Fc"/R + P815 target cells transfected with Cw3. On the other hand, NK clones displaying "specificity 1" and expressing the GL183-EB6 + phenotype failed to lyse Cw4 + target cells. Addition of the F(ab')2 fragments of either GL183 or EB6 mAb as well as the XA141 mAb of IgM isotype (specific for the EB6 molecules) completely restored the lysis of Cw3-transfected P815 cells by the Cw3-specific NK clones EX2 and EX4. Similarly, both the entire EB6 mAb, its F(ab')z fragment and the XA141 mAb reconstituted the lysis of C1R, a Fc'yR-target cell expressing Cw4 as the only serologically detected class I antigen. Thus, it appears that masking of different members of p58 molecules prevents recognition of "protective" MHC class I alleles and thus the delivering of inhibitory signals. Further support to the concept that p58 molecules represent a NK receptor delivering a negative signal was provided by experiments in which the entire anti-p58 mAbs (of IgG isotype) could inhibit the lysis of unprotected Fc'yR + P815 target cells, thus mimicking the inhibitory effect of MHC class I molecules. ecent data have substantially modified the general concept that human CD3-CD16 + CD56 + NK cells (1, 2) represent a homogeneous cytolytic lymphoid population displaying nonspecific, non-MHC-restricted functions. Thus, it has been shown that NK cells are capable of specific functions since they can discriminate among different normal allogeneic target cells (3,4). This ability is clonally distributed as different NK clones derived from single individuals display unique cytolytic patterns against allogeneic target cells (5-7). Thus, five distinct groups of alloreactive clones (each displaying a different specificity) have been identified (7). Genetic analysis (6, 7) and the use of cell transfectants (8) indicated that the target molecules recognized by NK clones are represented, at least in some instances, by HLA class I alleles (8-11). Whereas specific recognition of MHC molecules by alloreactive cytolytic T lymphocytes leads to triggering of their cytolytic function, in the case of NK lymphocytes, a given HLA allele (Cw3) was found to confer specific protection from lysis by a group of NK clones displaying a defined specificity (specific...

Deciphering the killer‐cell immunoglobulin‐like receptor system at super‐resolution for natural killer and T‐cell biology

“…Initial studies indicated a simple bipartite system in which KIR2DL2/3 recognizes HLA‐C allotypes with asparagine at residue 80 (the HLA‐C1 motif), and KIR2DL1 recognizes HLA‐C allotypes with lysine at residue 80 (the HLA‐C2 motif). Dimorphism at residue 44 of the KIR molecule causes these specificity differences, where KIR2DL2/3 has lysine and KIR2DL1 has methionine 36, 100, 104, 105. Crystal structures showed that K44 of KIR2DL2 forms a hydrogen bond with the N80 of HLA‐C1 99.…”

Cis interactions of immunoreceptors with MHC and non-MHC ligands

“…Inhibitory NK-cell receptors specific for classical MHC class I molecules belong to the mouse Ly49 (also known as KLRA) receptor family 6,7 and the human killer immunoglobulin-like receptor (KIR) family [8][9][10] . The molecular cloning of NK-cell receptors led to the identification of additional MHC class I receptors, which had not been predicted on the basis of functional experiments: human leukocyte immunoglobulin-like receptors (LILRs; also known as LIRs, ILTs or MIRs), and their orthologues, mouse paired immunoglobulin-like receptors (PIRs), as well as the heterodimeric CD94-NKG2 (NK group 2) receptors 11-14 (TABLE 1).…”

Cutting Edge: Susceptibility to Psoriatic Arthritis: Influence of Activating Killer Ig-Like Receptor Genes in the Absence of Specific HLA-C Alleles

“…2) and correlates well with their ability to inhibit NK cytolysis of target cells bearing those HLA allotypes. Specificity of inhibitory KIR for HLA-C allotypes is dictated to a large extent by the presence of asparagine or lysine at position 80 of the HLA-C molecule (3). KIR2DL1 recognizes group 2 HLA-C molecules, which have Lys 80 , whereas KIR2DL2 and KIR2DL3 prefer group 1 HLA-C molecules containing Asn 80 (3).…”

“…Specificity of inhibitory KIR for HLA-C allotypes is dictated to a large extent by the presence of asparagine or lysine at position 80 of the HLA-C molecule (3). KIR2DL1 recognizes group 2 HLA-C molecules, which have Lys 80 , whereas KIR2DL2 and KIR2DL3 prefer group 1 HLA-C molecules containing Asn 80 (3). Studies performed in vitro indicate that this division of specificity is not necessarily strict and may depend to some extent on bound peptide (4,5).…”