KIR2DL5 Can Inhibit Human NK Cell Activation Via Recruitment of Src Homology Region 2-Containing Protein Tyrosine Phosphatase-2 (SHP-2)

Abstract

Human NK cells use class I MHC-binding inhibitory receptors, such as the killer cell Ig-like receptor (KIR) family, to discriminate between normal and abnormal cells. Some tumors and virus-infected cells down-regulate class I MHC and thereby become targets of NK cells. Substantial evidence indicates that the mechanism of KIR-mediated inhibition involves recruitment of the protein tyrosine phosphatases, Src homology 2-containing protein tyrosine phosphatase-1 (SHP-1) and SHP-2, to two phosphorylated cytoplasmic immunoreceptor tyrosine-based inhibitory motifs (ITIMs). KIR2DL5 is a type II member of the KIR2D family with an atypical extracellular domain and an intracytoplasmic domain containing one typical ITIM and one atypical ITIM sequence. Although KIR2DL5 structure is expressed by ∼50% of humans and is conserved among primate species, its function has not been determined. In the present study, we directly compared functional and biochemical properties of KIR2DL5, KIR3DL1 (a type I KIR with two ITIMs), and KIR2DL4 (the only other type II KIR, which has a single ITIM) in a human NK-like cell line. Our results show that KIR2DL5 is an inhibitory receptor that can recruit both SHP-1 and SHP-2, and its inhibitory capacity is more similar to that of the cytoplasmic domain of KIR2DL4 than KIR3DL1. Interestingly, inhibition of NK cell cytotoxicity by KIR2DL5 was blocked by dominant-negative SHP-2, but not dominant-negative SHP-1, whereas both dominant-negative phosphatases can block inhibition by KIR3DL1. Therefore, the cytoplasmic domains of type II KIRs (2DL4 and 2DL5) exhibit distinct inhibitory capacities when compared with type I KIRs (3DL1), due to alterations in the canonical ITIM sequences.

Human KIR2DL5 Is an Inhibitory Receptor Expressed on the Surface of NK and T Lymphocyte Subsets

“…We have also shown that KIR2DL5 cross-linking is capable of inhibiting the NK cell cytotoxicity against a xenogeneic FcR ϩ target cell, an ability that likely involves the recruitment of the SHP-1 and SHP-2 phosphatases. The inhibitory effect and the binding of both phosphatases to KIR2DL5 in cells expressing naturally the receptor are in agreement with previous predictions based on the KIR2DL5 primary structure (23) and on the behavior of NK-92 cells transduced with FLAG-tagged-or chimerical molecules containing the KIR2DL5 cytoplasmic tail (38). The higher proportion of SHP-2 bound by KIR2DL5 in comparison with KIR2DL1 we have observed here (Fig.…”

“…KIR2DL5 has alleles with mRNA transcripts that are clonally distributed in NK and T lymphocytes and ones that are apparently not transcribed, the most common of which are, respectively, KIR2DL5A*001 and KIR2DL5B*002 (23,27). Finally, KIR2DL5 is predicted to encode a purely inhibitory receptor, according to its signaling motifs (two ITIMs, the second one having a noncanonical TxYxxL sequence, and a transmembrane region lacking charged amino acid residues) and to the behavior of cells transfected with tagged or chimerical KIR2DL5 constructs (23,38).…”

Ly49B Is Expressed on Multiple Subpopulations of Myeloid Cells

“…Consistent with this, we found that in transfected cells Ly49B does indeed associate with SHP-1 in a phosphorylationdependent manner. Ly49B also interacted with SHP-2, a protein tyrosine phosphatase that can associate with other Ly49 receptors (13,49,50) and forms an inhibitory complex with killer Ig-related receptors (51). It was also found to associate with SHIP-1, a phosphatase that is thought to play a major role in negative intracellular signaling via its degradation of phosphatidylinositol 3,4,5-trisphosphate.…”

KIR2DL5 alleles mark certain combination of activating KIR genes

“…4 Despite clustering together into a discrete lineage with high structural homologies, the KIR2DL5 and 2DL4 differ substantially in their amino-acid sequences, genomic locations, population distributions, level of transcriptions, cellsurface expressions, ligand specificities and signaling functions. [5][6][7][8][9] The KIR2DL4 gene is present on most KIR haplotypes and occurs at a frequency of 100% in most populations, whereas KIR2DL5 is variable among KIR haplotypes and thus differs considerably between populations in its frequency. [10][11][12] Two copies of the KIR2DL5 genes have been characterized, KIR2DL5A and KIR2DL5B, that show 99.5-99.7% identity in their coding sequences.…”

“…8,15 Although KIR2DL4 has been implicated in both inhibitory and activating functions, 6,[16][17][18] KIR2DL5 appears to be solely an inhibitory receptor. 7 Multiple sequences for both KIR2DL5A and KIR2DL5B loci have been characterized from individuals of different ethnic origins. 13 However, the nature of KIR2DL5 sequence polymorphism within distinct ethnic populations is not known.…”