ReviewA structural perspective on MHC class I recognition by killer cell immunoglobulin-like receptors
Introduction
Natural killer (NK) cells constitute a key component of the innate immune system and as such are able to respond more rapidly than T- or B-cell-mediated adaptive immunity. The cytolytic activity and cytokine production of NK cells is tightly regulated by an array of activating and inhibitory receptors on the cell surface (Raulet et al., 2001). A rather diverse collection of activating receptors engage various surface antigens on target cells, as well as certain class I MHC molecules. To date the ligands for many of these receptors remain unknown. In contrast, inhibitory receptors primarily recognize class I MHC molecules (Lanier, 1998, Long, 1999). Structurally, they comprise two distinct superfamilies, C-type lectin-like (Ly49 and CD94/NKG2) and immunoglobulin (Ig)-like (killer cell Ig-like receptors (KIR) and Ig-like transcripts (ILT) or leukocyte Ig-like receptors (LIR)). Ly49 and KIR both recognize classical class I MHC molecules and are believed to be functional orthologs. KIR exists exclusively in human and other primates, whereas Ly49 is found only in mice (Karlhofer et al., 1992). The heterodimeric CD94/NKG2 receptors, however, are conserved throughout the species along with their ligands, the non-classical class I MHC molecules, HLA-E in humans and Qa-1 in mice (Borrego et al., 1998, Braud et al., 1998, Lee et al., 1998, Vance et al., 1998).
Section snippets
The KIR superfamily
KIR are type I transmembrane glycoproteins with two to three extracellular C2-type Ig domains (Wagtmann et al., 1995a, Colonna and Samaridis, 1995, D’Andrea et al., 1995) and include both inhibitory and activating forms (Moretta et al., 1993, Moretta et al., 1995, Litwin et al., 1994, Dohring et al., 1996a). Activating forms have a relatively short cytoplasmic tail and contain a positively charged residue in the transmembrane region that interacts with specific activating adaptor proteins. The
Structure of KIR/HLA complexes
The first crystal structure of a KIR/HLA complex determined was that of KIR2DL2 bound with HLA-Cw3 and a nonamer self peptide GAVDPLLAL (GAV) from importin-α1 (Boyington et al., 2000). This structure revealed a common 1:1 binding mode, an elegant system for allotype recognition and limited peptide restriction. The 1:1 stiochiometry is also supported by analytical ultracentrifugation measurements (Sun and Schuck, unpublished data), gel-shift assays and surface plasmon resonance (SPR) studies (
Allotypic recognition of HLA molecules
Specificity is an integral characteristic of KIR/HLA interaction as various KIRs are restricted to particular groups of HLA alleles or allotypes. For example, KIR2DL1 and KIR2DS1 both interact with HLA-Cw2, 4, 5, 6, and 15, whereas KIR2DL2 and KIR2DL3 both recognize HLA-Cw1, 3, 7, and 8 allotypes. Earlier studies have implicated KIR2D residue 44 and the HLA-C heavy chain residue 80 as being critical in allotypic recognition (Winter and Long, 1997, Mandelboim et al., 1996). However, it was not
KIR/HLA binding displays a peptide preference
In addition to the class I MHC residues, the associated peptides are also crucial for KIR recognition (Wagtmann et al., 1995a, Zappacosta et al., 1997). TAP-deficient cells cultured at 26 °C in the absence of class I binding peptides, express “empty” class I MHC molecules on their cell surface. These class I molecules are unable to protect the target cells from lysis, indicating a requirement for peptide beyond merely stabilizing the class I molecule. Moreover it is also evident that peptides
KIR and TCR recognition modes reflect functional differences
A distinguishing characteristic of KIR/HLA interaction is that the interface is more conserved than TCR/HLA interfaces. For example, only eight out of 16 HLA-A2 residues in contact with the A6 TCR are conserved among HLA-A alleles. This reflects the very different functions of KIRs and TCRs in the innate and adaptive immune system, respectively. KIR molecules recognize large groups of HLA alleles bound to diverse peptides, essentially detecting whether or not various HLA allotypes are being
KIR/HLA interaction displays similarities with NKG2D/ULBP interaction
Two crystal structures of the activating NK cell receptor NKG2D complexed with its MHC-like ligands, ULBP3 and MICA, respectively have been recently determined, revealing similarities with KIR/HLA binding (Li et al., 2001, Radaev et al., 2001). NKG2D is a homodimeric receptor of the C-type lectin-like receptor (CTLR) superfamily. ULBP and MICA are stress induced ligands each consisting of α1α2-like domains of MHC molecules with no bound peptide. MICA has an α3 domain, whereas ULBP does not. The
KIR/HLA recognition is fundamentally different from Ly49A/H-Dd recognition
The recent crystal structure of a complex between the murine NK cell inhibitory receptor Ly49A and H-2Dd has unveiled a very different receptor/MHC binding mode (Tormo et al., 1999). In contrast to KIR, whose footprint on HLA-C superficially resembles that of TCRs on the class I MHC molecules, Ly49A has two distinct binding sites on H-2Dd (Fig. 7). The first binding site is located at the N-terminal region of the class I MHC α1 helix, whereas the second binding site is located below the H-2Dd
A Model for KIR/HLA clustering during immune synapse formation
Ligand induced receptor oligomerization is presumed to be a common mechanism for initiating receptor-mediated signaling. Some of the best understood examples to date are the growth hormone mediated dimerization of human growth hormone receptor and the erythropoietin(EPO) -induced conformational change in the EPO receptor (de Vos et al., 1992, Livnah et al., 1996). Since KIR receptors bear a structural resemblance to hematopoietic receptors, it has been proposed that KIR may form dimers upon
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