Killer Cell Immunoglobulin-like Receptors

Background

KIR is located on chromosome 19 (19q13.4) in the Leukocyte Receptor Complex (LRC). KIR is expressed on the surface of Natural Killer (NK) cells and some T cells. KIR do not undergo somatic rearrangement–a key difference from T-cell receptors. KIR interacts with HLA class I–their cognate ligand–to recognize and destroy unhealthy tissue cells while preventing the same from occurring to healthy cells. Therefore, NK cells play a role in fighting infections, resisting some cancers, pregnancy, and preventing autoimmunity. For further reading and references, I highly recommend the review article by Pollock, Harrison, and Norman on the immunogenetics and co-evolution of KIR and HLA class I.

KIR Locus

Adapted from Pollock, Harrison, and Norman. JACI: In Practice. 2022.

Gene	3DL3	2DS2	2DL2/3	2DL5B	2DS3	2DL1	2DL4	3DL1	3DS1	2DL5A	2DS5	2DS4	2DS1	3DL2
Function	Inhibit.	Activ.	Inhibit.	Inhibit.	Activ.	Inhibit.	Activ.	Inhibit.	Activ.	Inhibit.	Activ.	Activ.	Activ.	Inhibit.
Alleles	228	65	98	47	71	173	112	184	39	44	88	39	33	166
Allotypes	112	22	50	21	23	65	58	92	22	19	38	20	12	115
HLA Class I Ligand Motifs	B7H7	A*11 C1	B46:01 B73:01 C1 C2	PVR	?	C2	HLA-G	Bw4+ HLA-A and Bw4+ HLA-B	Bw4+ HLA-B and HLA-F	PVR	C2	A*11 HLA-C	C2	A3 A11

: Adapted from Pollock, Harrison, and Norman. JACI: In Practice. 2022.

KIR Diversity

KIR diversity is influenced by gene content variation and sequence variation. Distinct DNA sequences of KIR genes are called “alleles.” Distinct polypeptide sequences of KIR genes are called “allotypes.” Because different DNA sequences of KIR gene can lead to the same polypeptide, there are more alleles than allotypes for a given KIR gene.

KIR Diversity Concept	Definition
Gene Content Variation	Presence/absence, fusion, duplication
Sequence Variation	May alter ligand affinity or specificity, signal transduction ability, or surface expression (e.g., promoter activity, translation, intracellular trafficking)
Allele	Distinct DNA sequence
Allotype	Distinct polypeptide sequence

NK Cell Education

NK Cell Education (i.e., Arming, Licensing)	Corresponding Pairs of KIR and HLA Class I Ligands	Cytotoxicity and other Effector Abilities
Strong	Many	More
Weak	Few	Less

KIR Nomenclature

Inhibitory KIR

The main role of inhibitory KIR is to prevent cytotoxic NK and T cells from killing tissue cells–unless their HLA class I expression is lost or altered by infection or mutagenesis.

Activating KIR

Activating KIR help identify diseased cells for destruction by cytoxic NK and T cells. Binding of foreign peptides by HLA class I molecules retained by infected cells may be most critical for activating KIR.

Broad KIR Haplotypes

Broad KIR Haplotype	KIR Copy Number Variation	KIR Gene Organization	Activating KIR
A	Relatively stable	Generally non-variable	Less
B	Extensive	Highly variable	More

KIR Ligand Motifs

Adapted from Pollock, Harrison, and Norman. JACI: In Practice. 2022.

KIR Ligand Motif	HLA-A Allotypes	HLA-B Allotypes	HLA-C Allotypes
A3/A11	A*03, A*11
Bw4	A*23, A*24, A*32	B*07:27, B*08:02, B*08:03, (B13), B*15:13, B*15:16, B*15:17, B*15:23, B*15:24, B*15:36, B*15:43, B*15:67, B*27:01, B*27:02, B*27:03, B*27:04, B*27:05, B*27:07, B*37, B*38, B*40:13, B*40:19, B*44, B*47, B*49, B*51, B*52, B*53, B*56:07, B*57, B*58, B*59
C1	C*01, C*03, C*07, C*08, C*12:02, C*12:03, C*12:06, C*12:08, C*13, C*14, C*16	B*46, B*73
C2	C*02, C*03:07, C*04, C*05, C*06, C*12:04, C*12:05, C*12:07, C*14:04, C*15, C*16:02, C*17, C*18

KIR3DL1 and KIR3DS1

Because of significant non-allelic recombination in the KIR region, the distinction between KIR genes and alleles can be confusing. Specifically, KIR3DL1 and KIR3DS1 are alleles of the same gene. Of the KIR3DS1 allotypes–3DS1013 and 014–are observed with the greatest frequency in any population.