MHC-linked and un-linked class I genes in the wallaby

Background: MHC class I antigens are encoded by a rapidly evolving gene family comprising classical and non-classical genes that are found in all vertebrates and involved in diverse immune functions. However, there is a fundamental difference between the organization of class I genes in mammals and non-mammals. Non-mammals have a single classical gene responsible for antigen presentation, which is linked to the antigen processing genes, including TAP. This organization allows co-evolution of advantageous class Ia/ TAP haplotypes. In contrast, mammals have multiple classical genes within the MHC, which are separated from the antigen processing genes by class III genes. It has been hypothesized that separation of classical class I genes from antigen processing genes in mammals allowed them to duplicate. We investigated this hypothesis by characterizing the class I genes of the tammar wallaby, a model marsupial that has a novel MHC organization, with class I genes located within the MHC and 10 other chromosomal locations. Results: Sequence analysis of 14 BACs containing 15 class I genes revealed that nine class I genes, including one to three classical class I, are not linked to the MHC but are scattered throughout the genome. Kangaroo Endogenous Retroviruses (KERVs) were identified flanking the MHC un-linked class I. The wallaby MHC contains four non-classical class I, interspersed with antigen processing genes. Clear orthologs of non-classical class I are conserved in distant marsupial lineages. Conclusion: We demonstrate that classical class I genes are not linked to antigen processing genes in the wallaby and provide evidence that retroviral elements were involved in their movement. The presence of retroviral elements most likely facilitated the formation of recombination hotspots and subsequent diversification of class I genes. The classical class I have moved away from antigen processing genes in eutherian mammals and the wallaby independently, but both lineages appear to have benefited from this loss of linkage by increasing the number of classical genes, perhaps enabling response to a wider range of pathogens. The discovery of non-classical orthologs between distantly related marsupial species is unusual for the rapidly evolving class I genes and may indicate an important marsupial specific function

The E5 oncoprotein of BPV-4 does not interfere with the biosynthetic pathway of non-classical MHC class I

The major histocompatibility complex (MHC) class I region in mammals contains both classical and non-classical MHC class I genes. Classical MHC class I molecules present antigenic peptides to cytotoxic T lymphocytes, whereas non-classical MHC class I molecules have a variety of functions. Both classical and non-classical MHC molecules interact with natural killer cell receptors and may under some circumstances prevent cell death by natural killer cytotoxicity. The E5 oncoprotein of BPV-4 down-regulates the expression of classical MHC class I on the cell surface and retains the complex in the Golgi apparatus. The inhibition of classical MHC class I to the cell surface results from both the impaired acidification of the Golgi, due to the interaction of E5 with subunit c of the H+ V-ATPase, and to the physical binding of E5 to the heavy chain of MHC class I. Despite the profound effect of E5 on classical MHC class I, E5 does not retain a non-classical MHC class I in the Golgi, does not inhibit its transport to the cell surface and does not bind its heavy chain. We conclude that, as is the case for HPV-16 E5, BPV-4 E5 does not down-regulate certain non-classical MHC class I, potentially providing a mechanism for the escape of the infected cell from attack by both cytotoxic T lymphocytes and NK cells

Multiple expressed MHC class II loci in salmonids; details of one non-classical region in Atlantic salmon (Salmo salar)

<p>Abstract</p> <p>Background</p> <p>In teleosts, the Major Histocompatibility Complex (MHC) class I and class II molecules reside on different linkage groups as opposed to tetrapods and shark, where the class I and class II genes reside in one genomic region. Several teleost MHC class I regions have been sequenced and show varying number of class I genes. Salmonids have one major expressed MHC class I locus (UBA) in addition to varying numbers of non-classical genes. Two other more distant lineages are also identifyed denoted L and ZE. For class II, only one major expressed class II alpha (DAA) and beta (DAB) gene has been identified in salmonids so far.</p> <p>Results</p> <p>We sequenced a genomic region of 211 kb encompassing divergent MHC class II alpha (<it>Sasa-DBA</it>) and beta (<it>Sasa-DBB</it>) genes in addition to NRGN, TIPRL, TBCEL and TECTA. The region was not linked to the classical class II genes and had some synteny to genomic regions from other teleosts. Two additional divergent and expressed class II sequences denoted DCA and DDA were also identified in both salmon and trout. Expression patterns and lack of polymorphism make these genes non-classical class II analogues. <it>Sasa-DBB</it>, <it>Sasa-DCA </it>and <it>Sasa-DDA </it>had highest expression levels in liver, hindgut and spleen respectively, suggestive of distinctive functions in these tissues. Phylogenetic studies revealed more yet undescribed divergent expressed MHC class II molecules also in other teleosts.</p> <p>Conclusion</p> <p>We have characterised one genomic region containing expressed non-classical MHC class II genes in addition to four other genes not involved in immune function. Salmonids contain at least two expressed MHC class II beta genes and four expressed MHC class II alpha genes with properties suggestive of new functions for MHC class II in vertebrates. Collectively, our data suggest that the class II is worthy of more elaborate studies also in other teleost species.</p

Cytomegalovirus prevents antigen presentation by blocking the transport of peptide-loaded major histocompatibility complex class I molecules into the medial-Golgi compartment

Selective expression of murine cytomegalovirus (MCMV) immediate-early (IE) genes leads to the presentation by the major histocompatibility complex (MHC) class I molecule L a of a peptide derived from MCMV IE protein pp89 (Reddehase, M. J., J. B. Rothbard, and U. H. Koszinowski. 1989. Nature (Lond.). 337:651). Characterization of endogenous antigenic peptides identified the pp89 peptide as the nonapeptide msYPHFMFFNLt76 (del Val, M., H.-J. Schlicht, T. Ruppert, M. J. Reddehase, and U. H. Koszinowski. 1991. Cell. 66:1145). Subsequent expression of MCMV early genes prevents presentation of pp89 (del Val, M., K. Mfinch, M. J. Reddehase, and U. H. Koszinowski. 1989. Cell. 58:305). We report on the mechanism by which MCMV early genes interfere with antigen presentation. Expression of the IE promoter-driven bacterial gene lacZ by recombinant MCMV subjected antigen presentation of B-galactosidase to the same control and excluded antigen specificity. The La-dependent presence of naturally processed antigenic peptides also in nonpresenting cells located the inhibitory function subsequent to the step of antigen processing. The finding that during the E phase of MCMV gene expression the MHC class I heavy chain glycosylation remained in an Endo H-sensitive form suggested a block within the endoplasmic reticulum/c/s-Golgi compartment. The failure to present antigenic peptides was explained by a general retention of nascent assembled trimolecular MHC class I complexes. Accordingly, at later stages of infection a significant decrease of surface MHC class I expression was seen, whereas other membrane glycoproteins remained unaffected. Thus, MCMV E genes endow this virus with an effective immune evasion potential. These results also indicate that the formation of the trimolecular complex of MHC dass I heavy chain, ~2-microglobulin, and the finally trimmed peptide is completed before entering the medial-Golgi compartment

Characterization of the class I Major Histocompatibility Complex of the Macaca fascicularis

In an attempt to establish Macaca fascicularis as a viable animal model for disease studies, characterization of the MHC class I genes is necessary. The necessity arises because the MHC class I molecules have a functional role in immune response. Pig-tailed macaques Macaca nemestrina) and rhesus macaques (Macaca mulatta), two species closely related to Macaca fascicularis have been commonly used to model HIV infection and are well characterized in regards to their MHC class I molecules. As an initial step in establishing M. fascicularis as an animal model, we have cloned and characterized both classical and nonclassical MHC class I genes and have identified 21 MHC class I alleles orthologous to rhesus and pig-tailed macaque MHC-B, -E, and -F genes. No MHC-C locus was detected in the M. fascicularis. The MHC-B alleles from M. fascicularis, M. mulatta and M. nemestrina form a single highly polymorphic group

EXPRESSION OF A FUNCTIONAL CHIMERIC lg-MHC CLASS II PROTEIN

composed of the a- and ß-chains of the MHC class I1 I-E molecule fused to antibody V regions derived from anti-human CD4 mAb MT310. Expression vectors were constructed containing the functional, rearranged gene segments coding for the V region domains of the antibody H and L chains in place of the first domains of the complete structural genes of the I-E a- and ß-chains, respectively. Celltsr ansfected with both hybrid genes expressed a stable protein product on the cell surface. The chimeric molecule exhibited the idiotype of the antibody MT310 as shown by binding to the anti-idiotypic mAb 20-46. A protein of the anticipated molecular mass was immunoprecipitated witha nti-mouse IgG antiserum. Furthermore, human soluble CD4 did bind to thetr ansfected cell line, demonstrating that the chimeric protein possessed the binding capacity of the original mAb. Thus, the hybrid molecule retained: 1) the properties of a MHC class I1 protein with regardt o correct chain assembly and transport to the cell surface: as well as 2) the Ag binding capacity of the antibody genes used. Thgee neration of hybrid MHC class I1 molecules with highly specific, non-MHC-restricted bindingc apacities will be useful for studying MHC class 11-mediated effector functions such as selection of the T cell repertoire in thymus of transgenic mice

The porcine Major Histocompatibility Complex and related paralogous regions: a review

The physical alignment of the entire region of the pig major histocompatibility complex (MHC) has been almost completed. In swine, the MHC is called the SLA (swine leukocyte antigen) and most of its class I region has been sequenced. Over one hundred genes have been characterised, including the classical class I and class I-related genes, as well as the class II gene families. These results in swine provide new evidence for the striking conservation during the evolution of a general MHC framework, and are consistent with the location of the class I genes on segments referred to as permissive places within the MHC class I region. Recent results confirm the involvement of the SLA region in numerous quantitative traits

Allelic diversity and patterns of selection at the major histocompatibility complex class I and II loci in a threatened shorebird, the Snowy Plover (Charadrius nivosus)

Background: Understanding the structure and variability of adaptive loci such as the major histocompatibility complex (MHC) genes is a primary research goal for evolutionary and conservation genetics. Typically, classical MHC genes show high polymorphism and are under strong balancing selection, as their products trigger the adaptive immune response in vertebrates. Here, we assess the allelic diversity and patterns of selection for MHC class I and class II loci in a threatened shorebird with highly flexible mating and parental care behaviour, the Snowy Plover (Charadrius nivosus) across its broad geographic range. Results: We determined the allelic and nucleotide diversity for MHC class I and class II genes using samples of 250 individuals from eight breeding population of Snowy Plovers. We found 40 alleles at MHC class I and six alleles at MHC class II, with individuals carrying two to seven different alleles (mean 3.70) at MHC class I and up to two alleles (mean 1.45) at MHC class II. Diversity was higher in the peptide-binding region, which suggests balancing selection. The MHC class I locus showed stronger signatures of both positive and negative selection than the MHC class II locus. Most alleles were present in more than one population. If present, private alleles generally occurred at very low frequencies in each population, except for the private alleles of MHC class I in one island population (Puerto Rico, lineage tenuirostris). Conclusion: Snowy Plovers exhibited an intermediate level of diversity at the MHC, similar to that reported in other Charadriiformes. The differences found in the patterns of selection between the class I and II loci are consistent with the hypothesis that different mechanisms shape the sequence evolution of MHC class I and class II genes. The rarity of private alleles across populations is consistent with high natal and breeding dispersal and the low genetic structure previously observed at neutral genetic markers in this species

Induction of MHC Class I Expression by the MHC Class II Transactivator CIITA

Major histocompatibility complex (MHC) class I–deficient cell lines were used to demonstrate that the MHC class II transactivator (CIITA) can induce surface expression of MHC class I molecules. CIITA induces the promoter of MHC class I heavy chain genes. The site α DNA element is the target for CIITA-induced transactivation of class I. In addition, interferon-γ (IFNγ)–induced MHC class I expression also requires an intact site α. The G3A cell line, which is defective in CIITA induction, does not induce MHC class I antigen and promoter in response to IFNγ. Trans-dominant–negative forms of CIITA reduce class I MHC promoter function and surface antigen expression. Collectively, these data argue that CIITA has a role in class I MHC gene induction

Evolution of major histocompatibility complex class I and class II genes in the brown bear

International audienceBackground: Major histocompatibility complex (MHC) proteins constitute an essential component of the vertebrate immune response, and are coded by the most polymorphic of the vertebrate genes. Here, we investigated sequence variation and evolution of MHC class I and class II DRB, DQA and DQB genes in the brown bear Ursus arctos to characterise the level of polymorphism, estimate the strength of positive selection acting on them, and assess the extent of gene orthology and trans-species polymorphism in Ursidae . Results: We found 37 MHC class I, 16 MHC class II DRB, four DQB and two DQA alleles. We confirmed the expression of several loci: three MHC class I, two DRB, two DQB and one DQA. MHC class I also contained two clusters of non-expressed sequences. MHC class I and DRB allele frequencies differed between northern and southern populations of the Scandinavian brown bear. The rate of nonsynonymous substitutions (d N ) exceeded the rate of synonymous substitutions (d S ) at putative antigen binding sites of DRB and DQB loci and, marginally significantly, at MHC class I loci. Models of codon evolution supported positive selection at DRB and MHC class I loci. Both MHC class I and MHC class II sequences showed orthology to gene clusters found in the giant panda Ailuropoda melanoleuca. Conclusions: Historical positive selection has acted on MHC class I, class II DRB and DQB, but not on the DQA locus. The signal of historical positive selection on the DRB locus was particularly strong, which may be a general feature of caniforms. The presence of MHC class I pseudogenes may indicate faster gene turnover in this class through the birth-and-death process. South - north population structure at MHC loci probably reflects origin of the populations from separate glacial refugia