KIR is the abbreviation for “Killer-cell Immunoglobulin-like Receptor”. It is a family of receptors belonging to the immunoglobulin superfamily. In particular, they recognise Class I HLA molecules.
Molecular structure
The KIR receptor consists of three domains:
- An extracellulardomain: composed of two or three modules, it ensures ligand recognition.
- A classical transmembrane domain.
- An intracellular domain: long or short, it determines the function of the KIR based on the ITIM (Immunoreceptor Tyrosine-based Inhibition Motif) or ITAM (Immunoreceptor Tyrosine-based Activation Motif) sequences that it carries. Generally, long intra-cytoplasmic domains carry ITIM (inhibitory) sequences, while short intra-cytoplasmic domains carry ITAM (activating) sequences.
KIRs are named according to:
- The number of extracellular domains (2 or 3, KIR2D or KIR3D)
- The size of the intracytoplasmic fragment (long L or short S), and the pseudogenic nature, if applicable (P)
They are therefore categorised as follows:
- Two domains, long cytoplasmic fragment: KIR2DL1, KIR2DL2, KIR2DL3, KIR2DL4, KIR2DL5A, and KIR2DL5B
- Two domains, short cytoplasmic fragment: KIR2DS1, KIR2DS2, KIR2DS3, KIR2DS4, and KIR2DS5
- Three domains, long cytoplasmic fragment: KIR3DL1, KIR3DL2, and KIR3DL3
- Three domains, short cytoplasmic fragment: KIR3DS1
- Pseudogens: KIR2DP1 and KIR3DP1
In molecular biology, their nomenclature is similar to that of the HLA system.
KIR system characteristics
KIR system / HLA system interactions
The main known ligands of KIR receptors are Class I HLA molecules (classical or non-classical). This interaction allows the activation of the NK cell according to the missing-self theory (see NK cell activation).
Examples of KIR/HLA interactions
| HLA-Bw4 motif | HLA-C1 motif | HLA-C2 motif |
|---|---|---|
| KIR3DL1 KIR3DS1 | KIR2DL2 KIR2DL3 | KIR2DL1 KIR2DS1 |
| KIR2DS2 KIR2DS3 | ||
| KIR2DS4 |
Haplotypes and block transmission
The KIR genes are located on the long arm of chromosome 19, in the LRC (Leukocyte Receptor Complex) region. Just like the MHC region, this region contains many other genes involved in immunity.
The genetic proximity between the KIR gene loci explains the low probability of recombination occurring in the context of crossing-over. The transmission of alleles therefore occurs in a “block”, and like the HLA system, the KIR genes are organised in haplotype, from which a child inherits a paternal version and a maternal version.
https://www.ebi.ac.uk/ipd/kir/about/Illustration of the KIR genes within the so-called LRC (Leukocyte Receptor Complex) region
DAP: DNAX-Activating Proteins
CD66: CarcinoEmbryonic Antigen Cell Adhesion Molecule 6 (CEACAM6)
FcGRT: Fc (constant fragment) Gamma Receptor and Transporter
SIGLEC: Sialic acid binding IG-like LECtins
LILR: Leukocyte Immunoglobulin-Like Receptors
LAIR: Leukocyte Associated Immunoglobulin-like Receptors
KIR: Killer Immunoglobulin-Like Receptors
FcAR: Fc fragment of IgA Receptor
NCR1: Natural Cytotoxicity-triggering Receptor 1
In particular, there are two KIR haplotypes whose gene content differs:
- Haplotype A: contains 7 genes (and two pseudogenes), mainly KIRDL genes, with long intracellular domains where ITIM sequences can be grafted, which gives it an inhibitory profile. In this haplotype, all the genes are always present – except in very exceptional cases – and the polymorphism depends mainly on the allelic polymorphism of the inhibitory KIR genes, greater than that of the activating KIR genes.
- Haplotype B: may present up to 12 genes (and 2 pseudogenes), including 8 which are specific to haplotype B: KIR2DS2, KIR2DL2, KIR2DL5B, KIR2DS3, KIR3DS1, KIR2DL5A, KIR2DS5, and KIR2DS1. Haplotype B is defined by the presence of at least one of these 8 genes, even if it can also contain any gene from haplotype A. It mainly contains KIRDS genes with short intracellular domains associated with activating ITAM sequences, hence its activating profile. Its polymorphism resides mainly in the presence or absence of genes, which are less polymorphic on the allelic level.
Codominance
The gene products of both haplotypes are expressed on the surface of NK cells.
KIR gene polymorphism
In addition to polymorphism that arises from gene content, polymorphism is also allelic, as with HLA molecules. The combination of gene content variation and allelic polymorphism makes the KIR system likely even more polymorphic than the HLA system.
The polymorphism of KIR genes is deliberately reported in approximate numbers because the number of known alleles and proteins is constantly increasing, particularly since the massive sequencing of KIR genes. It should be noted that the inhibitory KIR genes are more polymorphic than the activating KIRs. Overall, the combination of gene (presence/absence of the gene) and allelic polymorphism is very important.
See https://www.ebi.ac.uk/ipd/kir/stats.html for updated figures.
| Gene | 2DL1 | 2DL2 | 2DL3 | 2DL4 | 2DL5A/B | 2DS1 | 2DS2 | 2DS3 |
|---|---|---|---|---|---|---|---|---|
| Alleles | ≈180 | ≈30 | ≈60 | ≈110 | ≈100 | ≈30 | ≈60 | ≈70 |
| Proteins | ≈70 | ≈10 | ≈30 | ≈60 | ≈40 | ≈10 | ≈20 | ≈20 |
| Gene | 2DS4 | 2DS5 | 3DL1 | 3DL2 | 3DL3 | 3DS1 | 2DP1 | 3DP1 |
|---|---|---|---|---|---|---|---|---|
| Alleles | ≈40 | ≈80 | ≈180 | ≈160 | ≈220 | ≈90 | ≈40 | ≈100 |
| Proteins | ≈20 | ≈30 | ≈90 | ≈110 | ≈110 | ≈30 | 0 (pseudogenic) | |
What should be remembered
KIRs are receptors carried by NK cells recognising, among other things, Class I HLA molecules (classical and non-classical). This recognition allows NK cells to activate, particularly when a cell down-regulates its HLA molecules, according to the missing-self theory. This is an important mechanism allowing the immune system to “catch up” with cells that would try to escape the cytotoxicity of CD8+ T cells by not or only minimally expressing their Class I HLA molecules.
The KIR system is highly polymorphic, probably more so than the HLA system. It is legitimate to think that the HLA/KIR combination in a donor/recipient couple is of interest, since it contributes to the intensity of the immune response, in particular cytotoxic cellular response.
