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MHC class I molecules and kirs in human history, health and survival

Key Points

  • MHC class I molecules and MHC-class-I-like molecules have been regulating the functions of lymphocytes for hundreds of millions of years. Today, MHC class I receptors are expressed by natural killer (NK) cells, γδ T cells and αβ T cells.

  • Some NK-cell receptors for MHC class I molecules are encoded by rapidly evolving gene families that create cellular diversity within the individual, distinguish individuals within populations and vary from one species to another. Regarding the latter, the difference between the Ly49 family of receptors in mice and the killer-cell immunoglobulin-like receptors (KIRs) in humans is paradigmatic.

  • Interactions between ligands of the HLA-C family and their cognate inhibitory KIRs are dominant in the regulation of human NK cells by KIRs. Both HLA-C molecules and their specific KIRs are of recent evolution and ascendancy, being found only in humans and some apes.

  • Balanced dimorphisms are characteristic of the KIR–HLA class I system of lymphocyte regulation: there are two types of HLA-C molecule (ligands known as C1 and C2) and two groups of KIR gene-family haplotype (known as A and B). Whereas the group A KIR haplotype mainly encodes inhibitory KIRs, the group B KIR haplotypes encode more activating KIRs.

  • The functions of NK cells in defence against infection and in embryo implantation during reproduction indicate that combinations of KIR and/or HLA polymorphisms will affect these functions. Recent studies have made several such correlations with pregnancy syndromes and susceptibility to infectious diseases.

  • Susceptibility to autoimmune disease has also been correlated with combinations of KIR and HLA class I molecules, as have beneficial and detrimental alloreactions after haematopoietic stem-cell transplantation.

  • Many of the clinical associations seem to be with particular activating KIRs, which do not seem to bind HLA class I molecules and for which ligands have not yet been determined. However, most of the data can be interpreted in terms of the group A and group B haplotype differences or in terms of differential degrees of inhibition that arise from the well-characterized inhibitory receptors.

Abstract

MHC class I molecules are ligands for the killer-cell immunoglobulin-like receptors (KIRs), which are expressed by natural killer cells and T cells. The interactions between these molecules contribute to both innate and adaptive immunity. KIRs and MHC class I molecules are encoded by unlinked polymorphic gene families that distinguish all but the most related individuals. Combinations of MHC class I and KIR variants influence resistance to infections, susceptibility to autoimmune diseases and complications of pregnancy, as well as outcome after haematopoietic stem-cell transplantation. Such correlations raise the possibility that interplay between KIR and MHC class I polymorphisms has facilitated human survival in the presence of epidemic infections and has influenced both reproduction and population growth.

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Figure 1: A hypothetical scheme for the evolution of lymphocytes during the 'big bang'.
Figure 2: The mouse Ly49 and human KIR loci have similar overall organization.
Figure 3: Common Caucasoid KIR haplotypes.
Figure 4: Hierarchy of inhibition mediated by KIR2DL binding to HLA-C.
Figure 5: Paired receptor model of KIR2DS-associated autoimmunity.

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Acknowledgements

Research in the author's laboratory was supported by grants from the National Institutes of Health (United States) and the Leukemia & Lymphoma Society (United States). The author thanks the referees for their suggestions.

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DATABASES

Entrez Gene

KIR2DL1

KIR2DL2

KIR2DL3

KIR2DL4

KIR2DL5

KIR2DS1

KIR2DS2

KIR2DS3

KIR2DS4

KIR2DS5

KIR3DL1

KIR3DL2

KIR3DL3

FURTHER INFORMATION

IPD-KIR Sequence Database

Glossary

B1 CELLS

The minority population of B cells. These cells express CD5, respond quickly to antigen, produce antibodies of broad specificity and do not depend on MHC-class-II-mediated T-cell help.

B2 CELLS

The main population of B cells. These cells do not express CD5, respond more slowly to antigen than B1 cells, produce antibodies of narrow specificity and depend on MHC-class-II-mediated T-cell help.

KIR LIGAND

(Killer-cell immunoglobulin-like receptor ligand). The parts of HLA class I molecules that form ligands for KIRs are sometimes called KIR ligands. C1, C2 and Bw4 are examples of KIR ligands. These are motifs that are present within groups of HLA-C molecules (C1 and C2 motifs in HLA-C1 and HLA-C2 molecules) and HLA-B molecules (Bw4 motif in HLA-Bw4).

KIR2DL

(Killer-cell immunoglobulin-like receptor 2DL). The KIR nomenclature gives the number of immunoglobulin domains, 2D or 3D, and the length of the cytoplasmic tail, long (L) or short (S), followed by a number to distinguish between KIRs with similar structures. The letter P instead of L or S denotes a pseudogene.

PSORIASIS

An autoimmune disease in which areas of skin become chronically inflamed and disrupted. It is often episodic, being triggered by injury, infection and other stresses. Worldwide, 80 million people have psoriasis; 10–30% of these individuals develop psoriatic arthritis, which usually affects finger and toe joints.

LINKAGE DISEQUILIBRIUM

Two genetic factors are in linkage disequilibrium when the frequency with which they occur together in a population departs from random expectation, as calculated by the product of their individual frequencies.

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Parham, P. MHC class I molecules and kirs in human history, health and survival. Nat Rev Immunol 5, 201–214 (2005). https://doi.org/10.1038/nri1570

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