KIRs

Killer-cell immunoglobulin-like receptors (KIRs) are a diverse family of receptors expressed mainly on natural killer (NK) cells and some T cell subsets. They regulate NK cell activity by recognizing specific human leukocyte antigen (HLA) class I molecules on potential target cells. Engagement of inhibitory KIRs with their MHC class I ligands dampens NK cell activation, while activating KIRs promote cytotoxic responses. This balance helps NK cells distinguish healthy cells from infected or malignant ones.

KIR genes are encoded by a highly variable gene cluster on chromosome 19 in humans. The locus shows extensive allelic diversity, copy-number variation, and rapid evolution across individuals and populations. Two broad haplotype groups, A and B, differ in gene content; haplotype A mainly carries inhibitory receptors, whereas haplotype B includes more activating receptors. The particular KIR gene repertoire in an individual shapes NK cell education and responsiveness.

Most KIRs are type I transmembrane glycoproteins with two to three immunoglobulin-like extracellular domains. Inhibitory KIRs typically possess long cytoplasmic tails containing ITIM motifs that recruit phosphatases to suppress signaling, while activating KIRs have short tails that associate with the adaptor molecule DAP12, delivering activating signals through ITAMs.

Ligands are primarily HLA class I molecules. Classic interactions include receptors that recognize HLA-C1 and HLA-C2 groups, as well as HLA-Bw4 and, for some receptors, HLA-A3/A11. Ligand affinity and specificity vary by receptor, influencing NK cell education (licensing) and effector function. KIR–HLA interactions also affect clinical outcomes in transplantation, pregnancy, infectious disease, autoimmunity, and cancer.