scholarly journals The Role of NKG2D Signaling in Inhibition of Cytotoxic T-Lymphocyte Lysis by the Murine Cytomegalovirus Immunoevasin m152/gp40

2007 ◽  
Vol 81 (22) ◽  
pp. 12564-12571 ◽  
Author(s):  
Amelia K. Pinto ◽  
Amanda M. Jamieson ◽  
David H. Raulet ◽  
Ann B. Hill
Keyword(s):  
Mhc Class I ◽  
Cytotoxic T Lymphocyte ◽  
Class I ◽  
Murine Cytomegalovirus ◽  
Small Subset ◽  
Small Contribution ◽  
Nkg2d Ligands ◽  
Infected Cells ◽  
The Impact

ABSTRACT Three proteins encoded by murine cytomegalovirus (MCMV)— gp34, encoded by m04 (m04/gp34), gp48, encoded by m06 (m06/gp48), and gp40, encoded by m152 (m152/gp40)—act together to powerfully impact the ability of primed cytotoxic CD8 T lymphocytes (CTL) to kill virus-infected cells. Of these three, the impact of m152/gp40 on CTL lysis appears greater than would be expected based on its impact on cell surface major histocompatibility complex (MHC) class I. In addition to MHC class I, m152/gp40 also downregulates the RAE-1 family of NKG2D ligands, which can provide costimulation for CD8 T cells. We hypothesized that m152/gp40 may impact CTL lysis so profoundly because it inhibits both antigen presentation and NKG2D-mediated costimulation. We therefore tested the extent to which m152/gp40's ability to inhibit CTL lysis of MCMV-infected cells could be accounted for by its inhibition of NKG2D signaling. As was predictable from the results reported in the literature, NKG2D ligands were not detected by NKG2D tetramer staining of cells infected with wild-type MCMV, whereas those infected with MCMV lacking m152/gp40 displayed measurable levels of the NKG2D ligand. To determine whether NKG2D signaling contributed to the ability of CTL to lyse these cells, we used a blocking anti-NKG2D antibody. Blocking NKG2D signaling did affect the killing of MCMV-infected cells for some epitopes. However, for all epitopes, the impact of m152/gp40 on CTL lysis was much greater than the impact of inhibition of NKG2D signaling. We conclude that the downregulation of NKG2D ligands by MCMV makes only a small contribution to the impact of m152/gp40 on CTL lysis and only for a small subset of CTL.

scholarly journals Infection with Listeria monocytogenes impairs sialic acid addition to host cell glycoproteins.

1994 ◽  
Vol 180 (6) ◽  
pp. 2137-2145 ◽  
Author(s):  
M S Villanueva ◽  
C J Beckers ◽  
E G Pamer
Keyword(s):  
Listeria Monocytogenes ◽  
Sialic Acid ◽  
Host Cell ◽  
Mhc Class I ◽  
Acid Content ◽  
Class I ◽  
Sialic Acid Content ◽  
Infected Cells ◽  
The Impact ◽  
Glycosylation Defect

Listeria monocytogenes is a facultative intracellular bacterium that causes severe disease in neonates and immunocompromised adults. Although entry, multiplication, and locomotion of Listeria in the cytosol of infected cells are well described, the impact of such infection on the host cell is unknown. In this report, we investigate the effect of L. monocytogenes infection on MHC class I synthesis, processing, and intracellular trafficking. We show that L. monocytogenes infection interferes with normal processing of N-linked oligosaccharides on the major histocompatibility complex (MHC) class I heavy chain molecule, H-2Kd, resulting in a reduced sialic acid content. The glycosylation defect is more pronounced as the infection progresses and results from interference with the addition of sialic acid rather than its removal by a neuraminidase. The effect is found in two different cell lines and is not limited to MHC class I molecules since CD45, a surface glycoprotein, and LGP120, a lysosomal glycoprotein, are similarly affected by L. monocytogenes infection. The glycosylation defect is specific for infection by L. monocytogenes since neither Trypanosoma cruzi nor Yersinia enterocolitica, two other intracellular pathogens, reproduces the effect. The resultant hyposialylation of H-2Kd does not impair its surface expression in infected cells. Diminished sialic acid content of surface glycoproteins may enhance host-defense by increasing susceptibility to lysis and promoting clearance of Listeria-infected cells.

scholarly journals Enhanced Intracellular Dissociation of Major Histocompatibility Complex Class I–associated Peptides: A Mechanism for Optimizing the Spectrum of Cell Surface–Presented Cytotoxic T Lymphocyte Epitopes

1997 ◽  
Vol 185 (8) ◽  
pp. 1403-1412 ◽  
Author(s):  
Alice J.A.M. Sijts ◽  
Eric G. Pamer
Keyword(s):  
Endoplasmic Reticulum ◽  
Major Histocompatibility Complex ◽  
Mhc Class I ◽  
T Lymphocyte ◽  
Half Life ◽  
Cytotoxic T Lymphocyte ◽  
Class I ◽  
Histocompatibility Complex ◽  
Infected Cells ◽  
Mhc Class I Molecules

Association of antigenic peptides with newly synthesized major histocompatibility complex (MHC) class I molecules occurs in the endoplasmic reticulum and is a critical early step for the initiation of cytotoxic T lymphocyte (CTL)-mediated immune defenses. Pathogen-derived peptides compete with a plethora of endogenous peptides for MHC class I grooves. We find that two H2-Kd–restricted peptides, which derive from the Listeria monocytogenes p60 antigen, accumulate in infected cells with different kinetics. Although competition assays suggest that both epitopes are bound with equivalent affinity, they dissociate from MHC class I molecules at markedly different rates. p60 217-225 forms complexes with H2-Kd with a half-life >6 h, while p60 449-457 dissociates from H2-Kd with a half-life of ∼1 h. We find that p60 449-457–H2-Kd complexes retained intracellularly with brefeldin A have a half-life of 30 min, and thus are less stable than surface complexes. While peptide dissociation from retained MHC class I molecules is enhanced, retained H2-Kd molecules maintain a remarkable capacity to bind new T cell epitopes. We find that intracellular H2-Kd molecules can bind new CTL epitopes for up to 3 h after their synthesis. Our studies provide a glimpse of peptide interaction with MHC class I molecules in the endoplasmic reticulum/proximal Golgi complex of intact, infected cells. We propose that the increased intracellular lability of peptide–MHC class I complexes may function to optimize the spectrum of peptides presented to T lymphocytes during cellular infection.

The Role of MHC Class I Expression in Rat NK Cell-Mediated Lysis of Syngeneic Tumor Cells and Virus-Infected Cells

Immunobiology ◽  
1996 ◽  
Vol 195 (3) ◽  
pp. 286-299 ◽  
Author(s):  
Katinka M. Giezeman-Smits ◽  
Peter J.K. Kuppen ◽  
N. Geeske Ensink ◽  
Alexander M.M. Eggermont ◽  
Frans Stals ◽  
...  
Keyword(s):  
Tumor Cells ◽  
Mhc Class I ◽  
Nk Cell ◽  
Class I ◽  
Syngeneic Tumor ◽  
Infected Cells

scholarly journals Cytotoxic T Lymphocyte Epitopes of HIV-1 Nef

2000 ◽  
Vol 191 (2) ◽  
pp. 239-252 ◽  
Author(s):  
Maria Lucchiari-Hartz ◽  
Peter M. van Endert ◽  
Grégoire Lauvau ◽  
Reinhard Maier ◽  
Andreas Meyerhans ◽  
...  
Keyword(s):  
Mhc Class I ◽  
T Lymphocyte ◽  
Antigen Processing ◽  
Cytotoxic T Lymphocyte ◽  
Rare Event ◽  
Class I ◽  
Direct Products ◽  
Active Debate ◽  
Hiv 1

Although a pivotal role of proteasomes in the proteolytic generation of epitopes for major histocompatibility complex (MHC) class I presentation is undisputed, their precise function is currently the subject of an active debate: do proteasomes generate many epitopes in definitive form, or do they merely generate the COOH termini, whereas the definitive NH2 termini are cleaved by aminopeptidases? We determined five naturally processed MHC class I ligands derived from HIV-1 Nef. Unexpectedly, the five ligands correspond to only three cytotoxic T lymphocyte (CTL) epitopes, two of which occur in two COOH-terminal length variants. Parallel analyses of proteasomal digests of a Nef fragment encompassing the epitopes revealed that all five ligands are direct products of proteasomes. Moreover, in four of the five ligands, the NH2 termini correspond to major proteasome cleavage sites, and putative NH2-terminally extended precursor fragments were detected for only one of the five ligands. All ligands are transported by the transporter associated with antigen processing (TAP). The combined results from these five ligands provide strong evidence that many definitive MHC class I ligands are precisely cleaved at both ends by proteasomes. Additional evidence supporting this conclusion is discussed, along with contrasting results of others who propose a strong role for NH2-terminal trimming with direct proteasomal epitope generation being a rare event.

scholarly journals Differential Influence on Cytotoxic T Lymphocyte Epitope Presentation by Controlled Expression of Either Proteasome Immunosubunits or Pa28

2000 ◽  
Vol 192 (4) ◽  
pp. 483-494 ◽  
Author(s):  
Thorbald van Hall ◽  
Alice Sijts ◽  
Marcel Camps ◽  
Rienk Offringa ◽  
Cornelis Melief ◽  
...  
Keyword(s):  
Mhc Class I ◽  
T Lymphocyte ◽  
Cytotoxic T Lymphocyte ◽  
Leukemia Virus ◽  
Class I ◽  
Ctl Epitope ◽  
Proteasome Subunits ◽  
Ifn Γ ◽  
Murine Leukemia

The proteasome is the principal provider of major histocompatibility complex (MHC) class I–presented peptides. Interferon (IFN)-γ induces expression of three catalytically active proteasome subunits (LMP2, LMP7, and MECL-1) and the proteasome-associated activator PA28. These molecules are thought to optimize the generation of MHC class I–presented peptides. However, known information on their contribution in vivo is very limited. Here, we examined the antigen processing of two murine leukemia virus-encoded cytotoxic T lymphocyte (CTL) epitopes in murine cell lines equipped with a tetracycline-controlled, IFN-γ–independent expression system. We thus were able to segregate the role of the immunosubunits from the role of PA28. The presence of either immunosubunits or PA28 did not alter the presentation of a subdominant murine leukemia virus (MuLV)-derived CTL epitope. However, the presentation of the immunodominant MuLV-derived epitope was markedly enhanced upon induction of each of these two sets of genes. Thus, the IFN-γ–inducible proteasome subunits and PA28 can independently enhance antigen presentation of some CTL epitopes. Our data show that tetracycline-regulated expression of PA28 increases CTL epitope generation without affecting the 20S proteasome composition or half-life. The differential effect of these IFN-γ–inducible proteins on MHC class I processing may have a decisive influence on the quality of the CTL immune response.

scholarly journals Vaccine-Elicited Memory Cytotoxic T Lymphocytes Contribute to Mamu-A*01-Associated Control of Simian/Human Immunodeficiency Virus 89.6P Replication in Rhesus Monkeys

2005 ◽  
Vol 79 (8) ◽  
pp. 4580-4588 ◽  
Author(s):  
Michael S. Seaman ◽  
Sampa Santra ◽  
Michael H. Newberg ◽  
Valerie Philippon ◽  
Kelledy Manson ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Mhc Class I ◽  
T Lymphocyte ◽  
Rhesus Monkeys ◽  
Cytotoxic T Lymphocyte ◽  
Class I ◽  
Immunodeficiency Virus ◽  
Memory Cytotoxic T Lymphocytes ◽  
The Impact ◽  
Ctl Responses

ABSTRACT The expression of particular major histocompatibility complex (MHC) class I alleles can influence the rate of disease progression following lentiviral infections. This effect is a presumed consequence of potent cytotoxic T-lymphocyte (CTL) responses that are restricted by these MHC class I molecules. The present studies have examined the impact of the MHC class I allele Mamu-A*01 on simian/human immunodeficiency virus 89.6P (SHIV-89.6P) infection in unvaccinated and vaccinated rhesus monkeys by exploring the contribution of dominant-epitope specific CTL in this setting. Expression of Mamu-A*01 in immunologically naive monkeys was not associated with improved control of viral replication, CD4+ T-lymphocyte loss, or survival. In contrast, Mamu-A*01 + monkeys that had received heterologous prime/boost immunizations prior to challenge maintained higher CD4+ T-lymphocyte levels and better control of SHIV-89.6P replication than Mamu-A*01 − monkeys. This protection was associated with the evolution of high-frequency anamnestic CTL responses specific for a dominant Mamu-A*01-restricted Gag epitope following infection. These data indicate that specific MHC class I alleles can confer protection in the setting of a pathogenic SHIV infection by their ability to elicit memory CTL following vaccination.

scholarly journals Recipients withIn UteroInduction of Tolerance Upregulated MHC Class I in the Engrafted Donor Skin

2014 ◽  
Vol 2014 ◽  
pp. 1-9
Author(s):  
Jeng-Chang Chen ◽  
Liang-Shiou Ou ◽  
Hsiu-Yueh Yu ◽  
Ming-Ling Kuo ◽  
Pei-Yeh Chang ◽  
...  
Keyword(s):  
Mhc Class I ◽  
Class I ◽  
Quantitative Real Time Pcr ◽  
Biological Phenomenon ◽  
Short Term ◽  
Donor Skin ◽  
Gene Transcripts ◽  
Infected Cells

The alterations in MHC class I expression play a crucial step in immune evasion of cancer or virus-infected cells. This study aimed to examine whether tolerized grafts modified MHC class I expression. FVB/N mice were rendered tolerant of C57BL/6 alloantigens byin uterotransplantation of C57BL/6 marrows. Postnatally, engrafted donor skins and leukocytes were examined for their MHC expression by quantitative real-time PCR and flow cytometry. Engrafted donor skins upregulated their MHC class I related gene transcripts after short-term (1~2 weeks) or long-term (>1 month) engraftment. This biological phenomenon was simultaneously associated with upregulation of TAP1 gene transcripts, suggesting an important role of TAP1 in the regulation of MHC class I pathway. The surface MHC class I molecules of H-2Kbin engrafted donor leukocytes consistently showed overexpression. Conclusively, the induction of allograft tolerance involved biological modifications of donor transplants. The overexpression of MHC class I within engrafted transplants of tolerant mice might be used as the tolerance biomarkers for identifying a state of graft tolerance.

scholarly journals Cellular and Molecular Requirements for Association of the Murine Cytomegalovirus Protein m4/gp34 with Major Histocompatibility Complex Class I Molecules

2006 ◽  
Vol 80 (12) ◽  
pp. 6048-6055 ◽  
Author(s):  
Xiuju Lu ◽  
Daniel G. Kavanagh ◽  
Ann B. Hill
Keyword(s):  
Major Histocompatibility Complex ◽  
Cell Surface ◽  
Antigen Presentation ◽  
Mhc Class I ◽  
Adenovirus Vector ◽  
Class I ◽  
Murine Cytomegalovirus ◽  
Histocompatibility Complex ◽  
Peptide Loading ◽  
Infected Cells

ABSTRACT The murine cytomegalovirus (MCMV) protein m4/gp34 is unique among known viral genes that target the major histocompatibility complex (MHC) class I pathway of antigen presentation in the following two ways: it is found in association with class I MHC molecules at the cell surface, and it inhibits antigen presentation without reducing cell surface class I levels. The current study was undertaken to define more clearly the structural and cellular requirements for m4/gp34 association with the MHC class I molecule Kb. We first assessed the role of the peptide-loading complex in m4/gp34-Kb association, using cell lines lacking TAP, tapasin, or β2m. m4/gp34-Kb complexes formed in the absence of TAP or tapasin, although not as efficiently as in wild-type cells. The expression of full-length and truncation mutants of m4/gp34 in a gutless adenovirus vector revealed that the transmembrane region of m4/gp34 was required for efficient association with the Kb heavy chain. However, the peptide-loading complex was not absolutely required for the association, since m4/gp34 readily formed complexes with Kb in detergent lysates. The addition of Kb-binding peptide to the detergent lysates facilitated but was not essential for the formation of the complexes. The ease of complex formation in detergent lysates contrasted with the small fractions of m4/gp34 and Kb that form complexes in infected cells, suggesting that the endoplasmic reticulum (ER) environment restricts access of m4/gp34 to Kb. Finally, although m4/gp34-Kb complexes could form when m4 was carried either by MCMV or by the adenovirus vector, they were only efficiently exported from the ER in MCMV-infected cells, suggesting that MCMV provides additional factors needed for transport of the complexes.

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