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

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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Characterization of a Murine Cytomegalovirus Class I Major Histocompatibility Complex (MHC) Homolog: Comparison to MHC Molecules and to the Human Cytomegalovirus MHC Homolog

Journal of Virology ◽

10.1128/jvi.72.1.460-466.1998 ◽

1998 ◽

Vol 72 (1) ◽

pp. 460-466 ◽

Cited By ~ 44

Author(s):

Tara L. Chapman ◽

Pamela J. Bjorkman

Keyword(s):

Major Histocompatibility Complex ◽

Heavy Chain ◽

Class I ◽

Major Histocompatibility ◽

Class I Mhc ◽

Endogenous Peptides ◽

Β2 Microglobulin ◽

Mhc Molecules ◽

Histocompatibility Complex ◽

Infected Cells

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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Recognition of class I major histocompatibility complex molecules by Ly-49: specificities and domain interactions.

Journal of Experimental Medicine ◽

10.1084/jem.183.4.1553 ◽

1996 ◽

Vol 183 (4) ◽

pp. 1553-1559 ◽

Cited By ~ 68

Author(s):

J Brennan ◽

G Mahon ◽

D L Mager ◽

W A Jefferies ◽

F Takei

Keyword(s):

Major Histocompatibility Complex ◽

Nk Cell ◽

Cell Subset ◽

Family Type ◽

Class I ◽

Target Cells ◽

Major Histocompatibility ◽

Binding Assays ◽

Mhc Molecules ◽

Histocompatibility Complex

Ly-49 is a family type II transmembrane proteins encoded by a gene cluster on murine chromosome 6. One member of this family, Ly-49A, is expressed by a natural killer (NK) cell subset, binds to class I major histocompatibility complex (MHC) molecules, and blocks the killing of target cells bearing the appropriate H-2 antigens. Here we show that another member of this family which is expressed by an NK cell subset, Ly-49C, recognizes H-2b and H-2d structures which are distinct from and overlapping with those recognized by Ly-49A. Interactions between Ly-49A and C and their class I ligands are entirely blocked by the antibodies 5E6, YE1/48, YE1/32, and A1, all of which were found to recognize epitopes contained within the carbohydrate recognition domain (CRD). However, cell-cell binding assays revealed that class I binding specificity is conferred by a combination of sequences within both the CRD and a 19-amino acid adjacent region. We also investigated the question of whether Ly-49A and C form dimers on cells which express both receptors. When coexpressed on COS cells, sequential immunoprecipitation demonstrated that these receptors pair exclusively as homodimers, with no evidence for heterodimeric structures. These observations provide insight into both the biochemical nature of the Ly-49 family as well as the receptor functions of Ly-49C on NK cells.

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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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GRP78, a Coreceptor for Coxsackievirus A9, Interacts with Major Histocompatibility Complex Class I Molecules Which Mediate Virus Internalization

Journal of Virology ◽

10.1128/jvi.76.2.633-643.2002 ◽

2002 ◽

Vol 76 (2) ◽

pp. 633-643 ◽

Cited By ~ 125

Author(s):

Kathy Triantafilou ◽

Didier Fradelizi ◽

Keith Wilson ◽

Martha Triantafilou

Keyword(s):

Major Histocompatibility Complex ◽

Cell Surface ◽

Major Histocompatibility Complex Class ◽

Class I ◽

Complex Class ◽

Major Histocompatibility ◽

Class I Mhc ◽

Mhc I ◽

Histocompatibility Complex ◽

Coxsackievirus A9

ABSTRACT It is becoming apparent that over the years cell infection by virus seems to have evolved into a multistep process in which many viruses employ distinct cell surface molecules for their attachment and cell entry. In this study the attachment and entry pathway of coxsackievirus A9 (CAV-9), a member of the Picornaviridae family, was investigated. It has been known that, although integrin αvβ3 is utilized as a receptor, its presence alone is insufficient for CAV-9 infection and that CAV-9 also requires a 70-kDa major histocompatibility complex class I (MHC-I)-associated protein (MAP-70) as a coreceptor molecule. We document by protein isolation and peptide sequencing that the 70-kDa protein is GRP78, a member of the heat shock protein 70 family of stress proteins. Furthermore we show by using fluorescence resonance energy transfer (FRET) that GRP78 is also expressed on the cell surface and associates with MHC-I molecules. In addition CAV-9 infection of permissive cells requires GRP78 and also MHC-I molecules, which are essential for virus internalization. The identification of GRP78 as a coreceptor for CAV-9 and the revelation of GRP78 and MHC-I associations have provided new insights into the life cycle of CAV-9, which utilizes integrin αvβ3 and GRP78 as receptor molecules whereas MHC-I molecules serve as the internalization pathway of this virus to mammalian cells.

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

Journal of Biological Chemistry ◽

10.1016/s0021-9258(19)49745-7 ◽

1992 ◽

Vol 267 (17) ◽

pp. 11669-11672

Author(s):

Y Yang ◽

K Früh ◽

J Chambers ◽

J.B. Waters ◽

L Wu ◽

...

Keyword(s):

Major Histocompatibility Complex ◽

Class I ◽

Antigenic Peptide ◽

Major Histocompatibility ◽

Class I Mhc ◽

Mhc Molecules ◽

Histocompatibility Complex ◽

Peptide Loading

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Adenovirus infection inhibits the phosphorylation of major histocompatibility complex class I proteins.

Journal of Experimental Medicine ◽

10.1084/jem.174.5.1159 ◽

1991 ◽

Vol 174 (5) ◽

pp. 1159-1166 ◽

Cited By ~ 16

Author(s):

R Lippé ◽

E Luke ◽

Y T Kuah ◽

C Lomas ◽

W A Jefferies

Keyword(s):

Major Histocompatibility Complex ◽

Cell Surface ◽

Cell Line ◽

Human Cell ◽

Human Cell Line ◽

Class I ◽

Major Histocompatibility ◽

Mhc Molecules ◽

Histocompatibility Complex ◽

Hla Molecules

Major histocompatibility complex (MHC) class I molecules act as peptide receptors to direct the recognition of foreign antigens by cytolytic T cells. The cell surface expression and trafficking of these peptide receptors is thought to be controlled by the conformation of the MHC molecule and possibly by the phosphorylation of the cytoplasmic portion of the heavy chain protein. It is of some interest that adenoviruses (Ads) have evolved proteins that interfere with the expression of MHC molecules. One of these proteins, called E3/19k, binds to newly synthesized MHC molecules in the rough endoplasmic reticulum (RER) and inhibits their trafficking to the cell surface. Here we show that during the infection of a human cell line with Ad2, the phosphorylation of the endogenous MHC molecules is inhibited. We also observe that the phosphorylation of the endogenous HLA molecules is grossly impaired in a human cell line transfected with the Ad2 EcoRI D fragment containing the E3/19k gene. We conclude that the E3/19k protein inhibits the phosphorylation of the MHC heavy chains and that this may be one of the important functions of this protein in infected cells. In addition, we show that a mutant of the E3/19k protein, which lacks an RER retention signal but which retains its ability to bind to HLA molecules, does not inhibit the phosphorylation of HLA molecules and that phosphorylated molecules are not Endo H sensitive. This suggests that HLA molecules are phosphorylated after leaving the medial-Golgi compartment, thus providing the most compelling evidence yet that HLA molecules are phosphorylated at or near the cell surface. Finally, to our knowledge, this is the first study under which the phosphorylation of MHC molecules is shown to be altered and may have some relevance for other pathogenic conditions.

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Altered Expression of TAP-1 and Major Histocompatibility Complex Class I in Laryngeal Papillomatosis: Correlation of TAP-1 with Disease

Clinical and Diagnostic Laboratory Immunology ◽

10.1128/cdli.7.1.79-85.2000 ◽

2000 ◽

Vol 7 (1) ◽

pp. 79-85 ◽

Cited By ~ 30

Author(s):

Andrea Vambutas ◽

Vincent R. Bonagura ◽

Bettie M. Steinberg

Keyword(s):

Major Histocompatibility Complex ◽

Cell Surface ◽

Clinical Course ◽

Hpv Infection ◽

Class I ◽

Immune Recognition ◽

Major Histocompatibility ◽

Class I Mhc ◽

Laryngeal Papilloma ◽

Histocompatibility Complex

ABSTRACT Recurrent respiratory papillomatosis (RRP) is an insidious disease caused by human papillomavirus (HPV) infection. It is characterized by a variable clinical course that can include frequent disease recurrence, significant morbidity, and occasional mortality. The mechanisms responsible for the variability in the clinical course and the persistence of latent HPV infection remain unknown. Effective T-cell-mediated clearance of HPV-infected cells may be defective in patients with RRP, leading to recurrent disease and failure to suppress latent HPV reactivation. This study describes the down-regulation of the transporter associated with antigen presentation (TAP-1) and the major histocompatibility complex (MHC) class I protein expression in laryngeal papilloma tissue biopsies and cell culture of primary explants. There was a statistically significant correlation between reduction of TAP-1 expression in biopsy tissues and rapid recurrence of disease. Patients with RRP had less frequent recurrence if their papillomas expressed TAP-1 at levels close to that of normal tissue, compared with those with very low expression of TAP-1, who had frequent recurrence (32 versus 5 weeks to the next surgical intervention). These findings suggest that HPV may evade immune recognition by down-regulating class I MHC cell surface expression via decreased TAP-1 levels. Expression of TAP-1 could be used for prognostic evaluation of disease severity. Gamma interferon was able to restore class I MHC expression at the surfaces of laryngeal papilloma cells in culture. This up-regulation of class I MHC antigen at the cell surface potentially allows the infected cell to become a target for the immune system again. This finding provides some promise for nonsurgical treatment of laryngeal papillomas.

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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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