Activating killer cell immunoglobulin-like receptor (Activating KIR)

Activating killer cell immunoglobulin-like receptors (KIRs) are transmembrane glycoproteins expressed on natural killer (NK) cells and a subset of T cells that play a pivotal role in modulating immune responses (UniProt: Q14954). Unlike inhibitory KIRs, activating KIRs (such as KIR2DS1 and KIR2DS2) possess short cytoplasmic tails that lack immunoreceptor tyrosine-based inhibitory motifs (ITIMs) and instead signal through the DAP12 adapter protein, which contains immunoreceptor tyrosine-based activation motifs (ITAMs) (PubMed: 10508250). These receptors specifically recognize Human Leukocyte Antigen C (HLA-C) ligands; for instance, KIR2DS1 binds to HLA-C2 group alleles, triggering NK cell degranulation and the secretion of pro-inflammatory cytokines like IFN-gamma (PubMed: 18364370). In oncology, activating KIRs are being explored as targets to enhance graft-versus-leukemia effects and improve the efficacy of NK cell-based immunotherapies (PubMed: 28615544). Furthermore, the interaction between maternal activating KIRs and fetal HLA-C is crucial for successful placentation, with certain combinations reducing the risk of preeclampsia (PubMed: 21441448). Therapeutic development currently focuses on monoclonal antibodies and CAR-NK cell constructs designed to selectively trigger these activating pathways to combat cancer and chronic infections.

Other names

KIR2DSKIR2DS1KIR2DS2KIR2DS3KIR2DS4KIR2DS5CD158Killer cell immunoglobulin-like receptor, short tailActivating KIRs

Activating KIRs function by binding to specific HLA-C ligands on target cells, which induces the recruitment and phosphorylation of the DAP12 adapter protein (PubMed: 10508250). This phosphorylation initiates a downstream signaling cascade involving Syk and ZAP-70 kinases, leading to calcium mobilization, NK cell degranulation, and the production of cytokines such as TNF-alpha and IFN-gamma (PubMed: 18364370). This process directly results in the lysis of the target cell, providing a critical defense mechanism against tumors and viral infections.