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Review
. 2008 Dec;20(6):343-52.
doi: 10.1016/j.smim.2008.06.003. Epub 2008 Jul 16.

The Yin and Yang of HLA and KIR in human disease

Smita Kulkarni  1 , Maureen P Martin, Mary Carrington
Affiliations
Review

The Yin and Yang of HLA and KIR in human disease

Smita Kulkarni et al. Semin Immunol. 2008 Dec.

Abstract

Killer cell immunoglobulin-like receptors (KIR) are expressed on natural killer (NK) cells and subsets of T cells. The KIR genes are polymorphic and the KIR gene complex is polygenic with varying numbers of inhibitory and activating receptors. HLA class I molecules serve as ligands for the KIR. Interactions of the independently segregating KIR and HLA loci are important for recognition of targets by NK cells as well as NK cell 'licensing'. Several disease association studies indicate a role for interactions between these loci in infectious diseases, autoimmune/inflammatory disorders, cancer and reproduction. Emerging functional data supports a mechanism based on a continuum of inhibition to activation through various compound KIR-HLA genotypes in diseases.

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Figures

Figure 1
Figure 1. Genomic organization of the KIR gene cluster
The KIR gene cluster is located on chromosome 19q13.4 within the Leukocyte Receptor Complex. KIR haplotypes vary extensively in gene content. The A haplotype is fixed in terms of gene content, but the B haplotypes are characterized by variable gene numbers (shown in brackets). Framework genes (pink boxes) are present on all haplotypes. The ancestral KIR gene 3DX1 is also shown.
Figure 2
Figure 2. HLA-ligand binding specificities for KIR
Alleles belonging to the KIR ligand groups HLA-C1/C2 and Bw4 80I/80T are listed in the boxes. The activating receptors KIR2DS2, 2DS1 and 3DS1 are thought to exhibit ligand specificity similar to the corresponding inhibitory counterparts, although their interactions are much weaker (depicted as smaller red broken arrows). The interaction of KIR3DL1 with Bw4 80I (dark blue arrow) is thought to be stronger than that with Bw4 80T (light blue arrow). Ligands for KIR2DL5, 2DS3, 2DS4, 2DS5 and 3DL3 have not been identified.
Figure 3
Figure 3. Functional model for KIR-HLA mediated hierarchy of inhibition
The cartoon shows possible KIR-HLA interactions in an individual homozygous for the A haplotype and homozygous for either HLA-C2 (left side) or HLA-C1 (right side), based on the findings of Ahlenstiel et al [49]. Interaction of KIR2DL1 with HLA-C2 results in strong inhibition that is difficult to overcome by simultaneous activating signals, and thus there is no killing of the target in this model. The weaker KIR2DL3-HLA-C1 interaction, on the other hand, can be overridden by signals through activating receptors upon appropriate ligand binding, resulting in lysis of the target.
Figure 4
Figure 4. Summary of KIR mediated NK cell activation/inhibition in diseases
Distinct KIR and HLA ligand pairs generate a hierarchy of NK cell activation. Both increased activation and inhibition are associated with susceptibility to and protection against a variety of diseases.
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