Activating killer-cell immunoglobulin-like receptors (aKIRs)

Activating killer-cell immunoglobulin-like receptors (aKIRs) are a group of transmembrane glycoproteins expressed on natural killer (NK) cells and a subset of T cells that play a pivotal role in the innate immune response. Structurally characterized by short cytoplasmic tails, aKIRs lack intrinsic signaling motifs and instead associate with the adaptor protein DAP12, which contains immunoreceptor tyrosine-based activation motifs (ITAMs) to initiate downstream signaling. These receptors recognize specific human leukocyte antigen (HLA) class I molecules, such as HLA-C1, HLA-C2, and HLA-Bw4, and their engagement triggers NK cell activation, leading to the release of cytotoxic granules and proinflammatory cytokines like interferon-gamma. In the context of autologous NK cells, aKIRs are essential for detecting "stressed" or "altered-self" cells, although their activity is often counterbalanced by inhibitory KIRs that maintain self-tolerance. Therapeutically, aKIRs are targeted to enhance anti-tumor immunity, particularly in hematological malignancies and solid tumors where tumor cells may downregulate HLA to escape T cell detection. While direct agonistic antibodies for aKIRs are challenging to develop due to high sequence homology with inhibitory KIRs, strategies such as blocking inhibitory KIRs (e.g., with lirilumab) or engineering CAR-NK cells with aKIR signaling domains are actively being explored. Additionally, the presence of specific aKIR genes, such as KIR2DS1 or KIR2DS2, is used as a biomarker to predict better outcomes in certain immunotherapies and hematopoietic stem cell transplantations. Conversely, overactivation of these receptors has been implicated in the pathogenesis of autoimmune diseases and pregnancy complications, making them potential targets for inhibitory modulation in those contexts.

Other names

Activating KIRKIR-SShort-tail KIRsCD158KIR2DS1KIR2DS2KIR2DS3KIR2DS4KIR2DS5KIR3DS1

Agonism of activating KIRs to enhance NK cell-mediated lysis of tumor or infected cells; or blockade of inhibitory KIRs to shift the balance toward activation via existing activating KIRs.