Killer-cell immunoglobulin-like receptor–Human leukocyte antigen class I interface (KIR–HLA interface)

The Killer-cell immunoglobulin-like receptor (KIR)–Human leukocyte antigen (HLA) class I recognition interface is a fundamental regulatory mechanism of the innate immune system, specifically governing the activation of natural killer (NK) cells (UniProt: P43626, P43627). Inhibitory KIRs (such as KIR2DL1, KIR2DL2, and KIR2DL3) bind to specific HLA class I molecules (predominantly HLA-C) on the surface of healthy cells to deliver signals that suppress NK cell-mediated lysis, a process known as self-recognition (Parham, P., 2005, Nature Reviews Immunology). Cancer cells often exploit this mechanism by maintaining HLA expression to evade immune detection, effectively using the KIR-HLA interface as a don't eat me signal (Purdy, A. K., & Campbell, K. S., 2009, Cancer Biology & Therapy). Therapeutic intervention focuses on using monoclonal antibodies, such as lirilumab (BMS-986015), to disrupt this interface and restore the NK cells' ability to identify and destroy malignant cells (ClinicalTrials.gov: NCT01687387). This interface is also highly polymorphic, meaning that the strength and specificity of the interaction vary significantly between individuals, influencing susceptibility to infections and autoimmune diseases. Consequently, targeting this interface represents a promising avenue in immuno-oncology, particularly in combination with other checkpoint inhibitors like PD-1 blockers. Beyond cancer, the KIR-HLA interface is critical in determining the outcome of hematopoietic stem cell transplantation and the risk of pregnancy complications like pre-eclampsia (PMID: 28923825).

Other names

KIR-MHC class I interactionNK cell inhibitory checkpointKIR-HLA-C interfaceKIR-HLA complex

Checkpoint inhibition by blocking the binding of inhibitory KIRs to HLA class I ligands, thereby preventing inhibitory signaling and promoting NK cell activation against target cells.