Ancient interlocus exon exchange in the history of the HLA-A locus.

Abstract The major histocompatibility complex (MHC) in humans and chimpanzees includes three classical class I loci, A, B and C, which encode glycoproteins expressed on the surface of all nucleated cells. There are also several nonclassical class I loci including E, which have more limited expression. By analyzing published sequences, we have shown that in exons 4 and 5, A locus alleles from both humans and chimpanzees are much more similar to E than to B or C alleles, whereas in exons 2 and 3 alleles from all three classical class I loci are much more similar to each other than any one is to E. We propose that some 20 million years ago, interlocus recombination led to the formation of a hybrid gene in which exons 2 and 3 were derived from the original A locus and exons 4 and 5 were derived from the E locus. The fact that such an ancient event can still be detected suggests that interlocus recombination is rare in the MHC and does not significantly contribute to MHC polymorphism, which is known to be extremely high. The present finding, however, supports Gilbert's idea that exons in a gene may occasionally be replaced by those from another gene in the evolutionary process.

Download Full-text

Human Cytomegalovirus Protein US2 Interferes with the Expression of Human HFE, a Nonclassical Class I Major Histocompatibility Complex Molecule That Regulates Iron Homeostasis

Journal of Virology ◽

10.1128/jvi.75.21.10557-10562.2001 ◽

2001 ◽

Vol 75 (21) ◽

pp. 10557-10562 ◽

Cited By ~ 48

Author(s):

Sayeh Vahdati Ben-Arieh ◽

Baruch Zimerman ◽

Nechama I. Smorodinsky ◽

Margalit Yaacubovicz ◽

Chana Schechter ◽

...

Keyword(s):

Major Histocompatibility Complex ◽

Human Cytomegalovirus ◽

Viral Protein ◽

Complex Molecule ◽

Class I ◽

Major Histocompatibility ◽

Class I Mhc ◽

Classical Class ◽

Histocompatibility Complex ◽

Nonclassical Class

ABSTRACT HFE is a nonclassical class I major histocompatibility complex (MHC) molecule that is mutated in the autosomal recessive iron overload disease hereditary hemochromatosis. There is evidence linking HFE with reduced iron uptake by the transferrin receptor (TfR). Using a panel of HFE and TfR monoclonal antibodies to examine human HFE (hHFE)-expressing cell lines, we demonstrate the expression of stable and fully glycosylated TfR-free and TfR-associated hHFE/β2m complexes. We show that both the stability and assembly of hHFE complexes can be modified by the human cytomegalovirus (HCMV) viral protein US2, known to interfere with the expression of classical class I MHC molecules. HCMV US2, but not US11, targets HFE molecules for degradation by the proteasome. Whether this interference with the regulation of iron metabolism by a viral protein is a means of potentiating viral replication remains to be determined. The reduced expression of classical class I MHC and HFE complexes provides the virus with an efficient tool for altering cellular metabolism and escaping certain immune responses.

Download Full-text

TL Genes in Asian Wild Mice: The Evolutionary Conserved Nonclassical Class I Genes of the Major Histocompatibility Complex

Genetics In Wild Mice ◽

10.1159/000424156 ◽

2015 ◽

pp. 159-177

Author(s):

Yuichi Obata ◽

Kazuo Moriwaki ◽

Toshihiko Shiroishi ◽

Yoko Satta ◽

Naoyuki Takahata ◽

...

Keyword(s):

Major Histocompatibility Complex ◽

Class I ◽

Major Histocompatibility ◽

Wild Mice ◽

Histocompatibility Complex ◽

Nonclassical Class

Download Full-text

The Murine Nonclassical Class I Major Histocompatibility Complex–like CD1.1 Molecule Protects Target Cells from Lymphokine-activated Killer Cell Cytolysis

Journal of Experimental Medicine ◽

10.1084/jem.189.3.483 ◽

1999 ◽

Vol 189 (3) ◽

pp. 483-491 ◽

Cited By ~ 29

Author(s):

Chew Shun Chang ◽

Laurent Brossay ◽

Mitchell Kronenberg ◽

Kevin P. Kane

Keyword(s):

Major Histocompatibility Complex ◽

Nk Cell ◽

Killer Cell ◽

Class I ◽

Target Cells ◽

Inhibitory Receptor ◽

Major Histocompatibility ◽

Lymphokine Activated Killer Cell ◽

Histocompatibility Complex ◽

Nonclassical Class

Classical class I major histocompatibility complex (MHC) molecules, as well as the nonclassical class I histocompatibility leukocyte antigen (HLA)-E molecule, can negatively regulate natural killer (NK) cell cytotoxicity through engagement of NK inhibitory receptors. We show that expression of murine (m)CD1.1, a nonpolymorphic nonclassical MHC class I–like molecule encoded outside the MHC, protects NK-sensitive RMA/S target cells from adherent lymphokine-activated killer cell (A-LAK) cytotoxicity. Passage of effector cells in recombinant interleukin (rIL)-2 enhanced protection by mCD1.1, suggesting an expansion of relevant A-LAK population(s) or modulation of A-LAK receptor expression. Murine CD1.1 conferred protection from lysis by rIL-2–activated spleen cells of recombination activating gene (Rag)-1−/− mice, which lack B and T cells, demonstrating that mCD1.1 can protect RMA/S cells from lysis by NK cells. An antibody specific for mCD1.1 partially restored A-LAK lysis of RMA/S.CD1.1 transfectants, indicating that cell surface mCD1.1 can confer protection from lysis; therefore, mCD1.1 possibly acts through interaction with an NK inhibitory receptor. CD1.1 is by far the most divergent class I molecule capable of regulating NK cell activity. Finally, mCD1.1 expression rendered RMA/S cells resistant to lysis by A-LAK of multiple mouse strains. The conserved structure of mCD1.1 and pattern of mCD1.1 resistance from A-LAK lysis suggest that mCD1.1 may be a ligand for a conserved NK inhibitory receptor.

Download Full-text

Different Evolutionary Histories in Two Subgenomic Regions of the Major Histocompatibility Complex

Genome Research ◽

10.1101/gr.9.6.541 ◽

1999 ◽

Vol 9 (6) ◽

pp. 541-549 ◽

Cited By ~ 2

Author(s):

Silvana Gaudieri ◽

Jerzy K. Kulski ◽

Roger L. Dawkins ◽

Takashi Gojobori

Keyword(s):

Major Histocompatibility Complex ◽

Homologous Recombination ◽

Hla Class I ◽

Gene Families ◽

Class I ◽

Major Histocompatibility ◽

Histocompatibility Complex ◽

Multicopy Gene ◽

History Of ◽

The Common

Two subgenomic regions within the major histocompatibility complex, the alpha and beta blocks, contain members of the multicopy gene families HLA class I, human endogenous retroviral sequence (HERV-16; previously known as P5 and PERB3), hemochromatosis candidate genes (HCG) (II, IV, VIII, IX), 3.8-1, and MIC (PERB11). In this study we show that the two blocks consist of imperfect duplicated segments, which contain linked members of the different gene families. The duplication and truncation sites of the segments are associated with retroelements. The retroelement sites appear to generate the imperfect duplications, insertions/deletions, and rearrangements, most likely via homologous recombination. Although the two blocks share several characteristics, they differ in the number and orientation of the duplicated segments. On the 62.1 haplotype, the alpha block consists of at least 10 duplicated segments that predominantly contain pseudogenes and gene fragments of the HLA class I and MIC (PERB11) gene families. In contrast, the beta block has two major duplications containing the genes HLA-B and HLA-C, and MICA(PERB11.1) and MICB(PERB11.2). Given the common origin between the blocks, we reconstructed the duplication history of the segments to understand the processes involved in producing the different organization in the two blocks. We then found that the beta block contains four distinct duplications from two separate events, whereas the alpha block is characterized by multisegment duplications. We will discuss these results in relation to the genetic content of the two blocks.

Download Full-text

Nonclassical behavior of the thymus leukemia antigen: peptide transporter-independent expression of a nonclassical class I molecule.

Journal of Experimental Medicine ◽

10.1084/jem.181.4.1433 ◽

1995 ◽

Vol 181 (4) ◽

pp. 1433-1443 ◽

Cited By ~ 41

Author(s):

H R Holcombe ◽

A R Castaño ◽

H Cheroutre ◽

M Teitell ◽

J K Maher ◽

...

Keyword(s):

Cell Surface ◽

Antigen Processing ◽

Class I ◽

Peptide Transporter ◽

Classical Class ◽

Histocompatibility Complex ◽

Antigen Peptide ◽

Specialized Function ◽

Kinetics Of ◽

Nonclassical Class

The thymus leukemia (TL) antigen is a major histocompatibility complex-encoded nonclassical class I molecule. Here we present data demonstrating that expression of the TL antigen, unlike other class I molecules, is completely independent of the function of the transporter associated with antigen processing (TAP). The TL antigen is expressed by transfected TAP-2-deficient RMA-S cells when these cells are grown at 37 degrees C. In transfected RMA cells, the kinetics of arrival of TL antigen on the cell surface are similar to those of a classical class I molecule. The kinetics are not altered in TAP-deficient RMA-S cells, demonstrating that surface TL expression in TAP-deficient cells is not due to the stable expression of a few molecules that leak out by a TAP-independent pathway. Soluble TL molecules produced by Drosophila melanogaster cells are highly resistant to thermal denaturation, unlike peptide-free classical class I molecules synthesized by these insect cells. In addition, these soluble TL molecules are devoid of detectable bound peptides. The results demonstrate that the TL antigen is capable of reaching the surface without bound peptide, although acquisition of peptide or some other ligand through a TAP-independent pathway cannot be formally excluded. We speculate that the ability of the TL antigen to reach the cell surface, under conditions in which other class I molecules do not, may be related to a specialized function of the TL molecule in the mucosal immune system, and possibly in the stimulation of intestinal gamma delta T cells.

Download Full-text