Killer-cell Immunoglobulin-like Receptors (KIRs) are a family of highly polymorphic receptors expressed on Natural Killer (NK) cells and some T-cell subsets. They are encoded by a gene cluster on chromosome 19q13.4 and regulate NK cell activity by recognising HLA class I molecules on target cells.

KIRs can be either inhibitory (long cytoplasmic tail, L) or activating (short cytoplasmic tail, S). This is encoded directly in the gene name: KIR2DL1 = 2 extracellular domains, Long tail (inhibitory); KIR2DS1 = 2 domains, Short tail (activating).

Unlike HLA genes on chromosome 6, KIR genes show copy number variation: individuals differ not only in allele sequences but in which genes they carry at all. The KIR locus is organized into two main haplotype classes:

• Haplotype A: a fixed set of mostly inhibitory genes with only KIR2DS4 as an activating receptor. More common in East Asian populations.
• Haplotype B: variable content with multiple activating KIR genes. More diverse; associated with stronger antitumor and anti-viral NK activity.

Framework genes (labeled FW throughout this tool) are present in virtually all individuals regardless of their A or B haplotype status. They include KIR3DL3, KIR2DP1, KIR3DP1, KIR2DL4, and KIR3DL2.

The KIR-HLA axis is central to NK cell education: inhibitory KIRs suppress NK killing of cells expressing the correct HLA ligand ("self"). When a tumor cell downregulates HLA: a common immune-evasion mechanism. The loss of inhibitory signal ("missing self") can activate NK cells.

For most KIR genes, allelic variation does not change the fundamental functional classification — different alleles of KIR2DL1, for example, all bind HLA-C group 2. However, two genes are exceptions where the specific allele can render the gene functionally absent despite being nominally "present" in the genotype:

KIR3DL1 — expression-level variation

KIR3DL1 alleles vary dramatically in surface expression level, which directly determines the strength of inhibitory signalling upon Bw4 binding. Three expression categories are recognised (Gardiner et al. 2001; Norman et al. 2007):

• High-expressing (e.g. KIR3DL1*001, *002, *008, *015): normal surface density; full inhibitory function when Bw4 ligand is present.
• Low-expressing (e.g. KIR3DL1*005, *006, *007, *020): reduced surface density; weaker inhibitory signalling. Clinically relevant in transplantation contexts.
• Null (e.g. KIR3DL1*004, *028, *030): no surface expression despite the gene being present. Individuals homozygous for null alleles are functionally KIR3DL1-negative — the Bw4/KIR3DL1 inhibitory interaction is absent regardless of HLA-Bw4 status.

When a null or low-expression KIR3DL1 allele is detected, the tool displays a ⚠️ warning icon next to the Type badge in the gene table. Hover over the icon for allele-specific details. This warning does not change the gene's presence status but indicates that the inhibitory interaction with Bw4 may be impaired or absent.

KIR2DS4 — deletion alleles

KIR2DS4 is the only activating KIR gene on the A haplotype. A subset of alleles (including *003 and *004) carry a 22-bp deletion that causes a frameshift and premature stop codon, producing a truncated protein that is retained intracellularly and not expressed on the cell surface (Pando et al. 2003). These deletion alleles are common — the majority of European individuals who carry KIR2DS4 carry at least one deletion allele.

When a deletion allele is detected, the tool displays a ⚠️ warning icon. Individuals carrying two deletion alleles are functionally KIR2DS4-negative despite the gene being scored as "present" by genotyping tools.

The KIR B-content score was defined by Cooley et al. (2010) as a clinically validated metric for predicting relapse risk after unrelated donor hematopoietic cell transplantation (URD-HCT) in AML. Donors with more B-haplotype genes show stronger graft-versus-leukemia (GvL) effects.

The locus is divided into centromeric and telomeric regions by a recombination site (RS). A B motif is present when any B-haplotype-defining gene is detected in that region:

• Centromeric B motif: KIR2DS2, KIR2DL2, or KIR2DS3
• Telomeric B motif: KIR3DS1, KIR2DL5A, KIR2DL5B, KIR2DS5, or KIR2DS1

Each region is scored independently based on known gene co-inheritance structure (Pyo et al. 2010). The key discriminators are:

• Centromeric: KIR2DL3 is the canonical Cen-A1 marker, present on virtually every A haplotype. Its presence alongside B-defining genes indicates Cen-A/B (score 1); its absence with B-defining genes present indicates Cen-B/B (score 2).
• Telomeric: KIR3DL1 and KIR3DS1 are paralogous genes on opposing haplotypes. Both present indicates Tel-A/B (score 1); only KIR3DL1 indicates Tel-A/A (score 0); only KIR3DS1 indicates Tel-B/B (score 2).

Four HLA ligand systems are evaluated when matching HLA-typed alleles to KIR genes:

• HLA-C group 1 (C1): Asn at position 80. Ligand for KIR2DL2 and KIR2DL3 (inhibitory). Recognised with low affinity by KIR2DS2 (activating).
• HLA-C group 2 (C2): Lys at position 80. Ligand for KIR2DL1 (inhibitory). Recognised with low affinity by KIR2DS1 (activating).
• HLA-Bw4: Supertypic epitope (positions 77-83 of HLA-B; also some HLA-A alleles: A*23, A*24, A*25, A*32). Ligand for KIR3DL1. Putative weak ligand for KIR3DS1.
• HLA-A3/A11: The HLA-A*03 and HLA-A*11 allele groups. Ligand for KIR3DL2. Requires HLA-A typing, which is not part of standard 3-locus (A/B/C) clinical panels but is reported by T1K.
• HLA-G: Any HLA-G allele. Ligand for KIR2DL4, with binding that is largely allele-independent. HLA-G is a non-classical locus not included in standard clinical HLA typing, but is reported by T1K alongside the classical loci.

When an inhibitory KIR is present but its cognate HLA ligand is absent from the target cell, the NK cell loses inhibitory signalling: the "missing self" signal that may promote NK-cell-mediated killing.

KIR genes excluded from the interaction table: KIR3DL3, KIR2DL5A, and KIR2DL5B have no experimentally confirmed HLA ligand and are therefore never shown in the KIR-HLA interaction table, regardless of whether they are present in the sample. Including them as "ligand unknown" rows would add no actionable information.

C1/C2 and Bw4 classification uses a reference set of common alleles embedded in this tool. For a complete allele-to-group list see the EBI KIR Ligand Calculator. Rare alleles outside the embedded reference will return "Unknown". HLA-A3/A11 and HLA-G interactions are only evaluated when a matching T1K HLA genotype file is uploaded, since these loci are not part of the standard manual HLA entry fields.

1. Robinson J et al. IPD — the Immuno Polymorphism Database. Nucleic Acids Res. 2015;43:D423–31. DOI: 10.1093/nar/gku1161 [IPD-KIR database; KIR gene nomenclature and allele assignments]
2. Cooley S et al. Donor selection for natural killer cell receptor genes leads to superior survival after unrelated transplantation for acute myelogenous leukemia. Blood. 2010;116(14):2411–9. DOI: 10.1182/blood-2010-05-283051 [B-content score definition and clinical validation]
3. Pyo C-W et al. Different patterns of evolution in the centromeric and telomeric regions of group A and B haplotypes of the human killer cell Ig-like receptor locus. PLoS ONE. 2010;5(12):e15115. DOI: 10.1371/journal.pone.0015115 [Canonical Cen/Tel motif structure; basis of motif-based scoring]
4. Parham P. MHC class I molecules and KIRs in human history, health and survival. Nat Rev Immunol. 2005;5(3):201-14. DOI: 10.1038/nri1570 [KIR-HLA ligand assignments and co-evolution]
5. Moretta A et al. Activating receptors and coreceptors involved in human natural killer cell-mediated cytolysis. Annu Rev Immunol. 2001;19:197–223. DOI: 10.1146/annurev.immunol.19.1.197 [Inhibitory vs activating KIR nomenclature and function]
6. Gardiner CM et al. Different NK cell-activating receptors preferentially recruit Rb+ or Ra− NK cells and regulate their responses differently. J Immunol. 2001;166(5):2992–3001. DOI: 10.4049/jimmunol.166.5.2992 [KIR3DL1 allelic expression variation — initial characterisation]
7. Norman PJ et al. Unusual selection on the KIR3DL1/S1 natural killer cell receptor in Africans. Nat Genet. 2007;39(9):1092–9. DOI: 10.1038/ng2111 [KIR3DL1 allele expression classification: null/low/high]
8. Martin MP et al. Epistatic interaction between KIR3DS1 and HLA-B delays the progression to AIDS. Nat Genet. 2002;31(4):429-34. DOI: 10.1038/ng887 [KIR3DS1/HLA-Bw4-80Ile association with HIV progression]
9. Leung W et al. Determinants of antileukemia effects of allogeneic NK cells. J Immunol. 2004;172(1):644-50. DOI: 10.4049/jimmunol.172.1.644 [KIR2DS1 C2 binding and GvL effects]
10. Middleton D & Gonzelez F. The extensive polymorphism of KIR genes. Immunology. 2010;129(1):8-19. DOI: 10.1111/j.1365-2567.2009.03208.x [KIR2DL4/HLA-G; KIR gene structure and diversity]
11. Pando MJ et al. KIR2DS4 is a product of gene conversion with KIR3DL2 that introduced specificity for HLA-A*11 while diminishing avidity for HLA-C. J Immunol. 2003;171(6):2804-11. DOI: 10.4049/jimmunol.171.6.2804 [KIR2DS4 ligand and deletion alleles]
12. Hansasuta P et al. Recognition of HLA-A3 and HLA-A11 by KIR3DL2 is peptide-specific. Eur J Immunol. 2004;34(6):1673-9. DOI: 10.1002/eji.200425089 [KIR3DL2/HLA-A3,A11 binding specificity]
13. Zhao X et al. T1K: efficient and accurate KIR and HLA genotyper for short-read sequencing data. Genome Res. 2023;33(10):1712-25. DOI: 10.1101/gr.277585.122 [T1K genotyping tool: one of the supported input formats]