Nicolai Wagtmann

Recruitment of Tyrosine Phosphatase HCP by the Killer Cell Inhibitory Receptor

Cytolysis of target cells by natural killer (NK) cells and by some cytotoxic T cells occurs unless prevented by inhibitory receptors that recognize MHC class I on target cells. Human NK cells express a p58 inhibitory receptor specific for HLA-C. We report association of the tyrosine phosphatase HCP with the p58 receptor in NK cells. HCP association was dependent on tyrosine phosphorylation of p58. Phosphotyrosyl peptides corresponding to the p58 tail bound and activated HCP in vitro. Furthermore, introduction of an inactive mutant HCP into an NK cell line prevented the p58-mediated inhibition of target cell lysis. These data imply that the inhibitory function of p58 is dependent on its tyrosine phosphorylation and on recruitment and activation of HCP.

Molecular clones of the p58 NK cell receptor reveal immunoglobulin-related molecules with diversity in both the extra- and intracellular domains

Recognition of major histocompatibility class I molecules on target cells by natural killer (NK) cells confers selective protection from NK-mediated lysis. Cross-linking of the p58 NK receptor, involved in the recognition of HLA-C alleles, delivers a negative signal that prevents target cell lysis. Molecular cloning of the p58 NK receptor reported here revealed a new member of the immunoglobulin superfamily. Five distinct p58 receptors, with sequence diversity in the immunoglobulin-related domains, were identified in a single individual. All NK clones tested expressed at least one p58 member. Three different types of transmembrane and cytoplasmic domains exist, even among receptors with closely related extracellular domains. These data revealed a repertoire of NK cells with clonally distributed p58 receptors exhibiting diversity in both extracellular and intracellular domains.

Killer cell inhibitory receptors specific for HLA-C and HLA-B identified by direct binding and by functional transfer

Abstract An inhibitory signal is delivered to natural killer (NK) cells and a subset of cytotoxic T cells upon recognition of HLA class 1 molecules on target cells. We demonstrate that soluble forms of killer cell inhibitory receptors (KIR) bind directly and specifically to HLA-C alleles on transfected cells. Furthermore, transfer of individual KIR Into NK clones reconstituted recognition of HLA-C on target cells, leading to inhibition of lysis. Using such functional reconstitution, a related KIR that confers specificity for some HLA-B alleles was also identified. These KIR share conserved tyrosine phosphorylation motifs in their cytoplasmic tails. Thus, a single receptor in NK cells provides both specificity for HLA class I on target cells and the Inhibitory signal that prevents lysis.

Killer cell inhibitory receptors: diversity, specificity, and function

Summary: NK cells selectively kill target cells that fail to express self‐MHC class I molecules. This selective killing results from a balance between inhibitory NK receptors specific for MHC class I molecules and activating receptors that are still largely unknown. Isolation of molecular clones for the human killer cell inhibitory receptors (KIR) revealed that KIR consist of a family of molecules with Ig ectodomains and cytoplasmic tails o f varying length. Soluble complexes of KIR and HLA‐C molecules established that KIR recognizes and binds to its ligand as an autonomous receptor. A functional expression system in human NK clones demonstrated that a single KIR can provide both recognition of MHC class 1 and delivery of a dominant negative signal to the NK cell. Functional evidence has been obtained for a role of Uie tyrosine phosphatase SHP‐1 in KIR‐mediated inhibition. The presence of a conserved molif used to recruit and activate SHP‐1 in the cytoplasmic tail of KIR and of the mouse Ly‐49 inhibitory receptor (otherwise structurally unrelated to KIR) represents an interesting case of evolutionary convergence. Furthermore, the motif led to the identification of other receptors with inhibitory potential, including a type I Ig‐like receptor shared by mouse mast cells and NK cells.

Natural killer cell receptors

The specificity in the recognition of hematopoietic target cells by natural killer cells is primarily provided by inhibitory receptors and several such receptors have been identified in the past year. Surprisingly, the recognition of MHC class I molecules by inhibitory receptors on human natural killer cells involves two different types of receptors, one with Ig domains (killer cell inhibitory receptor), and another with C-type lectin domains (CD94-NKG2). Mouse natural killer cells recognize MHC class I molecules through the C-type lectin Ly49 receptors but also express a receptor, of unknown ligand specificity, that is related to the killer cell inhibitory receptor.

Type I transmembrane receptor with inhibitory function in mouse mast cells and NK cells

The MHC class I-specific inhibitory receptors on human and mouse NK cells have surprisingly different structures. The mouse receptors (Ly-49) are type II transmembrane glycoproteins of the C-type lectin family, whereas the human receptors (killer cell inhibitory receptors (KIR)) belong to the Ig superfamily. This difference prompted a search for Ig-like inhibitory receptors in mice. Here we show that gp49, a mouse mast cell protein of unknown function but with sequence similarity to KIR, is expressed in NK cells. The gp49 cytoplasmic tail, containing a sequence related to an inhibitory motif shared by KIR and Ly-49, delivered a strong inhibitory signal in both human and mouse NK cells when substituted for a KIR cytoplasmic tail. These data show that Ig-like receptors with inhibitory properties exist in both species and that mouse mast and NK cells may recognize common inhibitory ligands.