View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector Immunity, Vol. 15, 363–374, September, 2001, Copyright 2001 by Cell Press Genetic and Functional Relationships Review between MHC and NK Receptor Genes John Trowsdale1 the human genome, notably at the central class III re- kbp. It 12ف Immunology Division gion, where there is over one gene per Pathology Department encodes the most polymorphic human proteins known University of Cambridge to date, the class I and class II molecules. Of the ex- Tennis Court Road pressed loci in the MHC, roughly 40% are associated Cambridge CB2 1QP with the immune system. Some of the main immune United Kingdom system genes are shown in Figure 2. They include the classical class I, HLA-A, -B, and -C, nonclassical HLA-E, -F, and -G, as well as “postmodern” MICA and HLA class I and NK receptors are encoded within MICB genes (MHC class I chain-related genes). There dense clusters of immune loci. The MHC, at 6p21.3, are also nonexpressed pseudogenes representing all and the complex containing the KIR loci, at 19q13.4, three groups of sequence. The products of classical polymorphic class I genes, HLA-A, B, and C, interact both feature variation in the number of genes, as well with T cell receptor (TCR) molecules as well as with the as sequence polymorphism. In addition to T cell recep- products of the killer immunoglobulin-like receptor (KIR) tors, several variable class I-related molecules interact genes expressed on natural killer cells and some T cells. with polymorphic NK receptors. Some of the lectin- The KIR interaction sites on class I molecules corre- related NK receptor genes, at 12p13.1, also have li- spond significantly with known dimorphisms in HLA-B gands belonging to the extended class I family. The (Bw4 and Bw6) (HLA-B loci carry “public” epitopes expanding clusters of class I-related sequences and which are dimorphisms of amino acids 77–83, dividing their receptors, some of which evolved recently, reveal HLA-B sequences into Bw4 and Bw6) and HLA-C (group further complexity in immune recognition of disease. 1 and group 2 [HLA-C loci are dimorphic for residues 77–80. In general, those with residues N77 and K80(Cw02, 04, 05, 06...)interact with KIR2DL1, while The MHC (major histocompatibility complex) and the those with residues S77 and N80(Cw01, 03, 07 . .) two sets of genes for NK (natural killer) receptors, the interact with KIR2DL2/3]). HLA-E, on the other hand, NKC (NK complex of lectin-related genes on chromo- interacts with products belonging to the lectin-like set some 12p13.1) and the LRC (leukocyte receptor com- of NK receptors in the natural killer complex (NKC). Ex- plex of immunoglobulin [Ig]-related genes on chromo- pression of the molecule depends on the presence of some 19q13.4), are large, dense clusters of immune loci. leader sequences from classical class I molecules, These complexes have some similar features, such as which are needed for HLA-E to reach the cell surface, the high levels of polymorphism, which may be main- where it then interacts with NKG2/CD94 ligand (Braud tained by resistance to infection. Diverse interactions et al., 1998). In mice, the Qa1 molecule performs a similar are emerging between the some of the main products function to HLA-E, interacting with the evolutionarily of MHC and NK clusters, class I molecules and NK re- conserved CD94/NKG2 heterodimer, although the two ceptors, respectively (Figure 1). These sets of polymor- class I genes may not be direct orthologs. The function phic cell surface molecules provide alternative ways of of HLA-F is not known, but it is capable of binding to recognizing disease and influencing immune responses. ILT2 and ILT4 receptors of the Ig superfamily, related The innate immune system, to which NK cells belong, to and mapping alongside the KIR genes (Lepin et al., has been overshadowed by adaptive immunity, with its 2000). HLA-G is restricted to the placenta, where it is rearranging receptors. The emerging genetic and func- thought to help protect the fetus from rejection by the tional relationships between the MHC and NK genes immune system of the mother (King et al., 2000). and their products help to provide a more balanced view The MIC genes are distant relatives of MHC class I of immune recognition. The growing numbers of NK- molecules, expressed on intestinal mucosa and on other related receptors and their class I-like partners reveal cells in response to stress (Bahram et al., 1994). These sophisticated recognition systems in which the adaptive genes contain heat shock elements in their promoters. immune system is modulated in novel ways. These inter- They do not appear to function in presentation of patho- ␣␤ actions have implications for understanding susceptibil- gen-derived peptides to T cells with TCRs but are ␥␦ ity to infection as well as autoimmunity and cancer. broadly recognized by intraepithelial T cells with TCRs. They can also act as costimulatory molecules for CD8␣␤ T cells after induction of expression by viruses MHC Genes such as CMV (Groh et al., 2001). MICA and MICB are both -Mbp of DNA on chromo 4ف The human MHC covers polymorphic, with an unusual distribution of a number of some 6p21.3 and contains over 220 identified loci (MHC variant amino acids in their extracellular ␣1, ␣2, and ␣3 Sequencing Consortium, 1999). It has been divided into domains. MIC molecules are neither associated with three regions: class II (centromeric), class III, and class ␤2 microglobulin nor bound peptide, and only a small I (telomeric) with extended class I and class II regions on remnant of a groove remains. Null alleles have been either side. This is one of the most gene-dense regions of recorded, including haplotypes with no functional MICA or MICB expression, and mice do not appear to have 1 Correspondence: [email protected] MIC genes. MIC proteins interact with a common recep- Immunity 364 Figure 1. Interactions of the Products of Some MHC Class I-Related Genes with Receptors Encoded in the NKC and the LRC Some of the main sets of genes in the NKC, MHC, and LRC complexes are shown at their approximate chromosomal locations. Known receptor:ligand interactions are depicted by dotted lines. tor, comprising NKG2D homodimers, associated with as BTN and BTL, related to the milk protein butyrophilin, the adaptor DAP10 (Wu et al., 1999). The NKG2D genes are located in the class II-III border as well as the ex- are located in the NKC on chromosome 12. A MICA tended class I region. The encoded proteins are distantly crystal structure has been obtained as well as a complex related to the expanding family of coreceptor molecules of MICA with NKG2D (Li et al., 2001). Recently, other exemplified by B7.1 and B7.2 that are revealing increas- sets of sequences weakly related to class I have been ing complexity in costimulatory patterns regulating T found to interact with NKG2D. The human ULBP gene cell functions (Coyle and Gutierrez-Ramos, 2001). products, encoded on chromosome 6q24 (Cosman et MHC Evolution Is Restless al., 2001), and mouse RAEs (mouse chromosome 10- A good idea is worth imitating. Dot-matrix analysis re- syntenic to human 6q) (Yokoyama, 2000), may also indi- veals that both class I and class II genes, while main- cate stress. These molecules resemble the membrane- taining the same basic structure, have undergone re- distal parts of HLA class I molecules, the ␣1 and ␣2 peated duplication and loss, maintaining a handful of domains, attached to the cell surface by GPI linkage favored genes in most species, by a continuous “birth- (Cosman et al., 2001). and-death” process (Shiina et al., 1999). As novel gene Like class I, class II genes can be divided into classical family members emerged, they have diverged, some (HLA-DP, -DQ, and -DR) and nonclassical (HLA-DM have survived, and others have been lost. Interspersed and -DO). All class II molecules are heterodimers, en- within these variable regions are several islands of coded by pairs of loci. In all cases except HLA-DO, the unique sequence (e.g., LMP/TAP and RING3) which did A and B chain genes are adjacent in the genome. HLA- not obviously originate by cis-duplication. The expan- DM and -DO do not function directly as presenting mole- sions and contractions of sequences have apparently cules, and they do not have peptide binding grooves. taken place against a background of framework loci At steady state, these molecules are expressed mainly that are invariant in number and conserved in different in MIIC vesicles, where they aid in peptide loading onto species (Amadou, 1999). The class I region has been classical class II. Another set of MHC-encoded genes subjected to the most interspecies duplication events, plays a major role in loading peptides onto class I, and haplotypes can differ markedly in the number of namely TAP1/TAP2, LMP2/LMP7, and TAPBP, encoding loci (Pichon et al., 1996). Certain species of mice are the TAPASIN molecule (Lehner and Trowsdale, 1998). estimated to contain hundreds of class I sequences, Other immune system loci in the complex include cell most of which have become pseudogenes (Delarbre et surface molecules, such as an activating receptor al., 1992). One mechanism proposed to explain the gen- NKp30(1C7) on NK cells, IgSF molecules such as MOG, eration of the reiterated duplications involves capture complement components C2, C4, and factor B, inflam- by retroelements such as retroviruses (Dawkins et al., matory mediators such as TNF, and three HSP70 loci.