Major histocompatibility complex (MHC)-encoded HAM2 is necessary for antigenic peptide loading onto class I MHC molecules.

ABSTRACT Both human and murine cytomegaloviruses (HCMV and MCMV) down-regulate expression of conventional class I major histocompatibility complex (MHC) molecules at the surfaces of infected cells. This allows the infected cells to evade recognition by cytotoxic T cells but leaves them susceptible to natural killer cells, which lyse cells that lack class I molecules. Both HCMV and MCMV encode class I MHC heavy-chain homologs that may function in immune response evasion. We previously showed that a soluble form of the HCMV class I homolog (UL18) expressed in Chinese hamster ovary cells binds the class I MHC light-chain β2-microglobulin and a mixture of endogenous peptides (M. L. Fahnestock, J. L. Johnson, R. M. R. Feldman, J. M. Neveu, W. S. Lane, and P. J. Bjorkman, Immunity 3:583–590, 1995). Consistent with this observation, sequence comparisons suggest that UL18 contains the well-characterized groove that serves as the binding site in MHC molecules for peptides derived from endogenous and foreign proteins. By contrast, the MCMV homolog (m144) contains a substantial deletion within the counterpart of its α2 domain and might not be expected to contain a groove capable of binding peptides. We have now expressed a soluble version of m144 and verified that it forms a heavy chain–β2-microglobulin complex. By contrast to UL18 and classical class I MHC molecules, m144 does not associate with endogenous peptides yet is thermally stable. These results suggest that UL18 and m144 differ structurally and might therefore serve different functions for their respective viruses.

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Ly-49 mediates EL4 lymphoma adhesion to isolated class I major histocompatibility complex molecules.

Journal of Experimental Medicine ◽

10.1084/jem.179.3.1011 ◽

1994 ◽

Vol 179 (3) ◽

pp. 1011-1015 ◽

Cited By ~ 105

Author(s):

K P Kane

Keyword(s):

Major Histocompatibility Complex ◽

Gene Transfection ◽

Negative Regulator ◽

Class I ◽

Major Histocompatibility ◽

Cell Surface Molecule ◽

Class I Mhc ◽

Mhc Molecules ◽

Histocompatibility Complex ◽

T Lymphomas

Ly-49 is a recently identified cell surface molecule expressed on a subpopulation of natural killer (NK) cells and certain T lymphomas. It has been suggested, based on gene transfection and antibody blocking studies, that Ly-49 is a negative regulator of NK lytic activity, possibly through an interaction with target cell class I molecules. However, it has not been demonstrated that class I molecules indeed serve as ligands for Ly-49. We have found that T lymphomas expressing Ly-49 bind isolated class I major histocompatibility complex (MHC) molecules but not class II molecules immobilized on plastic. Adhesion to class I molecules was not found with T lymphomas lacking Ly-49 expression. The Ly-49 expressing EL4 lymphoma bound Dd, Dk, and Kb, but not Kd, Kk, or Db, thus demonstrating a restricted pattern of class I adhesion. The observed cell adhesion was class I density dependent, and binding to Dd and Dk was extensively inhibited by the A1 monoclonal antibody directed against Ly-49. These results provide direct evidence for Ly-49 serving as a receptor for a subset of class I MHC molecules.

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Antigenic peptide loading into major histocompatibility complex class I is driven by the substrate N-terminus

CCS Chemistry ◽

10.31635/ccschem.021.202000657 ◽

2021 ◽

pp. 1-27

Author(s):

Mengna Lin ◽

Honglin Xu ◽

Yi Shi ◽

Lin-Tai Da

Keyword(s):

Major Histocompatibility Complex ◽

Major Histocompatibility Complex Class ◽

Class I ◽

Antigenic Peptide ◽

Complex Class ◽

Major Histocompatibility ◽

Histocompatibility Complex ◽

Peptide Loading ◽

N Terminus

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HHV-7 U21 exploits Golgi quality control carriers to reroute class I MHC molecules to lysosomes

Molecular Biology of the Cell ◽

10.1091/mbc.e19-07-0363 ◽

2020 ◽

Vol 31 (3) ◽

pp. 196-208

Author(s):

Aaron T. Dirck ◽

Melissa L. Whyte ◽

Amy W. Hudson

Keyword(s):

Quality Control ◽

Major Histocompatibility Complex ◽

Viral Protein ◽

Class I ◽

Major Histocompatibility ◽

Class I Mhc ◽

Complex Molecules ◽

Mhc Molecules ◽

Histocompatibility Complex

U21 is a viral protein that forms hetero-oligomers with class I major histocompatibility complex molecules and reroutes them to lysosomes. It is shown that U21 exits from the Golgi in a distinct clathrin-independent carrier that also carries unfolded and aggregated proteins to lysosomes.

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Human Herpesvirus 7 U21 Downregulates Classical and Nonclassical Class I Major Histocompatibility Complex Molecules from the Cell Surface

Journal of Virology ◽

10.1128/jvi.01782-09 ◽

2010 ◽

Vol 84 (8) ◽

pp. 3738-3751 ◽

Cited By ~ 20

Author(s):

Nathan A. May ◽

Nicole L. Glosson ◽

Amy W. Hudson

Keyword(s):

Major Histocompatibility Complex ◽

Cell Surface ◽

Infected Cell ◽

Nk Cell ◽

Human Herpesvirus ◽

Class I ◽

Major Histocompatibility ◽

Class I Mhc ◽

Mhc Molecules ◽

Histocompatibility Complex

ABSTRACT Herpesviruses have evolved numerous strategies to evade detection by the immune system. Notably, most of the herpesviruses interfere with viral antigen presentation to cytotoxic T lymphocytes (CTLs) by removing class I major histocompatibility complex (MHC) molecules from the infected cell surface. Clearly, since the herpesviruses have evolved an extensive array of mechanisms to remove class I MHC molecules from the cell surface, this strategy serves them well. However, class I MHC molecules often serve as inhibitory ligands for NK cells, so viral downregulation of all class I MHC molecules should leave the infected cell open to NK cell attack. Some viruses solve this problem by selectively downregulating certain class I MHC products, leaving other class I products at the cell surface to serve as inhibitory NK cell ligands. Here, we show that human herpesvirus 7 (HHV-7) U21 binds to and downregulates all of the human class I MHC gene products, as well as the murine class I molecule H-2Kb. HHV-7-infected cells must therefore possess other means of escaping NK cell detection.

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Presentation of Cytosolic Glycosylated Peptides by Human Class I Major Histocompatibility Complex Molecules in Vivo

Journal of Experimental Medicine ◽

10.1084/jem.190.1.145 ◽

1999 ◽

Vol 190 (1) ◽

pp. 145-150 ◽

Cited By ~ 74

Author(s):

John S. Haurum ◽

Ingelise Bjerring Høier ◽

Gemma Arsequell ◽

Anne Neisig ◽

Gregorio Valencia ◽

...

Keyword(s):

Major Histocompatibility Complex ◽

Posttranslational Modifications ◽

Cytotoxic T Lymphocyte ◽

Class I ◽

Major Histocompatibility ◽

Human Class ◽

Class I Mhc ◽

Mhc Molecules ◽

Histocompatibility Complex

Antigens presented by class I major histocompatibility complex (MHC) molecules for recognition by cytotoxic T lymphocytes consist of 8–10-amino-acid-long cytosolic peptides. It is not known whether posttranslationally modified peptides are also presented by class I MHC molecules in vivo. Many different posttranslational modifications occur on cytoplasmic proteins, including a cytosolic O-β-linked glycosylation of serine and threonine residues with N-acetylglucosamine (GlcNAc). Using synthetic glycopeptides carrying the monosaccharide O-β-GlcNAc substitution on serine residues, we have shown that glycopeptides bind efficiently to class I MHC molecules and elicit a glycopeptide-specific cytotoxic T lymphocyte response in mice. In this study, we provide evidence that peptides presented by human class I MHC molecules in vivo encompass a small, significant amount of glycopeptides, constituting up to 0.1% of total peptide. Furthermore, we find that carbohydrate structures present on glycopeptides isolated from class I MHC molecules are dominated by the cytosolic O-β-GlcNAc substitution, and synthetic peptides carrying this substitution are efficiently transported by TAP (transporter associated with antigen presentation) into the endoplasmic reticulum. Thus, in addition to unmodified peptides, posttranslationally modified cytosolic peptides carrying O-β-linked GlcNAc can be presented by class I MHC molecules to the immune system.

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Epitopes of the class I major histocompatibility complex (MHC-I) recognized in the syngeneic or allogeneic context predominantly linked to antigenic peptide loading to its binding groove

Clinical & Experimental Immunology ◽

10.1111/j.1365-2249.2006.03130.x ◽

2006 ◽

Vol 145 (2) ◽

pp. 372-379

Author(s):

P. Nguyen van Binh ◽

H. T. Duc

Keyword(s):

Major Histocompatibility Complex ◽

Class I ◽

Antigenic Peptide ◽

Major Histocompatibility ◽

Mhc I ◽

Histocompatibility Complex ◽

Peptide Loading ◽

Binding Groove

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Novel full-length major histocompatibility complex class I allele discovery and haplotype definition in pig-tailed macaques

10.1101/186494 ◽

2017 ◽

Author(s):

Matthew R. Semler ◽

Roger W. Wiseman ◽

Julie A. Karl ◽

Michael E. Graham ◽

Samantha M. Gieger ◽

...

Keyword(s):

Major Histocompatibility Complex ◽

Full Length ◽

Class I ◽

Major Histocompatibility ◽

Class I Mhc ◽

Mhc I ◽

Pacific Biosciences ◽

Histocompatibility Complex ◽

Immunodeficiency Virus ◽

The Impact

AbstractPig-tailed macaques (Macaca nemestrina, Mane) are important models for human immunodeficiency virus (HIV) studies. Their infectability with minimally modified HIV makes them a uniquely valuable animal model to mimic human infection with HIV and progression to acquired immunodeficiency syndrome (AIDS). However, variation in the pig-tailed macaque major histocompatibility complex (MHC) and the impact of individual transcripts on the pathogenesis of HIV and other infectious diseases is understudied compared to rhesus and cynomolgus macaques. In this study, we used Pacific Biosciences single-molecule real-time circular consensus sequencing to describe full-length MHC class I (MHC-I) transcripts for 194 pig-tailed macaques from three breeding centers. We then used the full-length sequences to inferMane-AandMane-Bhaplotypes containing groups of MHC-I transcripts that co-segregate due to physical linkage. In total, we characterized full-length open reading frames (ORFs) for 313Mane-A,Mane-B, andMane-Isequences that defined 86Mane-Aand 106Mane-BMHC-I haplotypes. Pacific Biosciences technology allows us to resolve theseMane-AandMane-Bhaplotypes to the level of synonymous allelic variants. The newly defined haplotypes and transcript sequences containing full-length ORFs provide an important resource for infectious disease researchers as certain MHC haplotypes have been shown to provide exceptional control of simian immunodeficiency virus (SIV) replication and prevention of AIDS-like disease in nonhuman primates. The increased allelic resolution provided by Pacific Biosciences sequencing also benefits transplant research by allowing researchers to more specifically match haplotypes between donors and recipients to the level of nonsynonymous allelic variation, thus reducing the risk of graft-versus-host disease.

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