Killer cell immunoglobulin-like receptor–human leukocyte antigen mismatch (KIR–HLA mismatch) in natural killer cell-mediated cytotoxicity (KIR–HLA mismatch)

The **killer cell immunoglobulin-like receptor–human leukocyte antigen mismatch ("KIR–HLA mismatch") context refers to an immunogenetic situation where natural killer (NK) cells from one individual encounter target cells lacking specific HLA class I molecules that would normally engage their inhibitory receptors.** NK cells express both activating and inhibitory receptors; among the most important are the **killer-cell immunoglobulin-like receptors (KIRs)**, which recognize motifs on **HLA class I molecules**, especially certain alleles such as those in the HLA-C group or those expressing Bw4 epitopes. When there is a lack of engagement between an individual's inhibitory KIRs and their corresponding HLA ligands—such as after transplantation from a donor with different HLA types—NK cells become more likely to attack target cells due to loss of inhibition ("missing-self recognition")[2][3][7]. This phenomenon has been exploited therapeutically, particularly in hematopoietic stem cell transplantation for leukemia, where selecting donors whose NK cells are alloreactive against recipient leukemia can enhance graft-versus-leukemia effects without increasing graft-versus-host disease risk[3]. The clinical impact depends on detailed genotyping of both donor and recipient for relevant **inhibitory/activating KIR genes and their cognate HLA ligands**, making it a complex but powerful approach in personalized medicine[1][5]. While not itself a single molecular drug target, this mechanism underpins several therapeutic strategies aiming to harness innate immunity against cancer or prevent transplant rejection.

Other names

KIR–HLA incompatibilityKiller-cell immunoglobulin-like receptor and human leukocyte antigen class I mismatchNK alloreactivity via KIR-HLA epitope incompatibility

Drugs or interventions leveraging this mechanism act by: Enhancing NK cell activation through reduced inhibitory signaling when donor-recipient pairs are mismatched for inhibitory KIR ligands on HLA class I. Promoting graft-versus-leukemia effects without increasing graft-versus-host disease risk.