Interferon-α and interferon-γ differentially affect pancreatic β-cell phenotype and function

1998 ◽  
Vol 275 (1) ◽  
pp. C25-C32 ◽  
Author(s):  
Manuel E. Baldeón ◽  
Taehoon Chun ◽  
H. Rex Gaskins
Keyword(s):  
Cell Line ◽  
Mhc Class I ◽  
Antigen Processing ◽  
Surface Expression ◽  
Class I ◽  
Cell Surface Expression ◽  
Cell Phenotype ◽  
Pancreatic Β Cell ◽  
Β Cell ◽  
Ifn Γ

To better clarify individual roles of interferon (IFN)-α and IFN-γ in β-cell pathology during the onset of type 1 diabetes mellitus, we compared the effects of these cytokines on insulin production and major histocompatibility complex (MHC) gene expression in pancreatic β-cell lines. IFN-γ but not IFN-α decreased secreted and intracellular insulin concentrations in βTC6-F7 and βTC3 cells. Likewise, IFN-γ but not IFN-α treatment of β-cells upregulated mRNA expression of MHC class IA antigen-processing genes and surface expression of class IA molecules. Alternatively, class IA MHC expression was upregulated by IFN-γ and IFN-α in the P388D1 macrophage cell line. The observation of constitutive Ifn-α6mRNA expression by a differentiated β-cell line substantiates previous indications that local expression of IFN-α in islets may trigger insulitis. Evidence that IFN-γ, a product of infiltrating leukocytes, directly decreases β-cell glucose sensitivity and increases MHC class IA cell surface expression supports the postulate that IFN-γ magnifies the insulitic process.

scholarly journals Modulation of Transporter Associated with Antigen Processing (TAP)-Mediated Peptide Import into the Endoplasmic Reticulum by Flavivirus Infection

2001 ◽  
Vol 75 (12) ◽  
pp. 5663-5671 ◽  
Author(s):  
Frank Momburg ◽  
Arno Müllbacher ◽  
Mario Lobigs
Keyword(s):  
Endoplasmic Reticulum ◽  
Cell Surface ◽  
Mhc Class I ◽  
Antigen Processing ◽  
Surface Expression ◽  
Class I ◽  
Peptide Transport ◽  
Cell Surface Expression ◽  
Flavivirus Infection ◽  
Mhc Class I Molecules

ABSTRACT In contrast to many other viruses that escape the cellular immune response by downregulating major histocompatibility complex (MHC) class I molecules, flavivirus infection can upregulate their cell surface expression. Previously we have presented evidence that during flavivirus infection, peptide supply to the endoplasmic reticulum is increased (A. Müllbacher and M. Lobigs, Immunity 3:207–214, 1995). Here we show that during the early phase of infection with different flaviviruses, the transport activity of the peptide transporter associated with antigen processing (TAP) is augmented by up to 50%. TAP expression is unaltered during infection, and viral but not host macromolecular synthesis is required for enhanced peptide transport. This study is the first demonstration of transient enhancement of TAP-dependent peptide import into the lumen of the endoplasmic reticulum as a consequence of a viral infection. We suggest that the increased supply of peptides for assembly with MHC class I molecules in flavivirus-infected cells accounts for the upregulation of MHC class I cell surface expression with the biological consequence of viral evasion of natural killer cell recognition.

scholarly journals Crystal structures of lysophospholipid-bound MHC class I molecules

2020 ◽  
Vol 295 (20) ◽  
pp. 6983-6991 ◽  
Author(s):  
Yoko Shima ◽  
Daisuke Morita ◽  
Tatsuaki Mizutani ◽  
Naoki Mori ◽  
Bunzo Mikami ◽  
...  
Keyword(s):  
Cell Surface ◽  
Crystal Structures ◽  
Mhc Class I ◽  
Antigen Processing ◽  
Surface Expression ◽  
Class I ◽  
Cell Surface Expression ◽  
Peptide Antigens ◽  
Histocompatibility Complex ◽  
Mhc Class I Molecules

Newly synthesized major histocompatibility complex (MHC) class I proteins are stabilized in the endoplasmic reticulum (ER) by binding 8–10-mer-long self-peptide antigens that are provided by transporter associated with antigen processing (TAP). These MHC class I:peptide complexes then exit the ER and reach the plasma membrane, serving to sustain the steady-state MHC class I expression on the cell surface. A novel subset of MHC class I molecules that preferentially bind lipid-containing ligands rather than conventional peptides was recently identified. The primate classical MHC class I allomorphs, Mamu-B*098 and Mamu-B*05104, are capable of binding the N-myristoylated 5-mer (C14-Gly-Gly-Ala-Ile-Ser) or 4-mer (C14-Gly-Gly-Ala-Ile) lipopeptides derived from the N-myristoylated SIV Nef protein, respectively, and of activating lipopeptide antigen-specific cytotoxic T lymphocytes. We herein demonstrate that Mamu-B*098 samples lysophosphatidylethanolamine and lysophosphatidylcholine containing up to a C20 fatty acid in the ER. The X-ray crystal structures of Mamu-B*098 and Mamu-B*05104 complexed with lysophospholipids at high resolution revealed that the B and D pockets in the antigen-binding grooves of these MHC class I molecules accommodate these lipids through a monoacylglycerol moiety. Consistent with the capacity to bind cellular lipid ligands, these two MHC class I molecules did not require TAP function for cell-surface expression. Collectively, these results indicate that peptide- and lipopeptide-presenting MHC class I subsets use distinct sources of endogenous ligands.

scholarly journals Magnitude of Alloresponses to MHC Class I/II Expressing Human Cardiac Myocytes Is Limited by Their Intrinsic Ability to Process and Present Antigenic Peptides

2003 ◽  
Vol 10 (2-4) ◽  
pp. 213-226 ◽  
Author(s):  
J. Bruce Sundstrom ◽  
Kimberley C. Jollow ◽  
Veronique Braud ◽  
Francois Villinger ◽  
Andrew J. McMichael ◽  
...  
Keyword(s):  
Cardiac Myocytes ◽  
Mhc Class I ◽  
Mhc Class Ii ◽  
Influenza A ◽  
Antigen Processing ◽  
Class I ◽  
Target Cells ◽  
Mrna Levels ◽  
Antigenic Peptides ◽  
Ifn Γ

In this investigation we have explored the relationship between the weak allogenicity of cardiac myocytes and their capacity to present allo-antigens by examining the ability of a human cardiac myocyte cell line (W-1) to process and present nominal antigens. W-1 cells (HLA-A*0201 and HLA-DR β1*0301) pulsed with the influenza A matrix 1 (58-66) peptide (M1) were able to serve as targets for the HLA-A*0201 restricted CTL line PG, specific for M1-peptide. However, PG-CTLs were unable to lyse W-1 target cells infected with a recombinant vaccinia virus expressing the M1 protein (M1-VAC). Pretreatment of these M1-VAC targets with IFN-γ partially restored their ability to process and present the M1 peptide. However, parallel studies demonstrated that IFN-γ pretreated W-1's could not process tetanus toxin (TT) or present the TT(830-843) peptide to HLA-DR3 restricted TT-primed T cells. Semi-quantitative RT-PCR measurements revealed significantly lower constitutive levels of expression for MHC class I, TAP-1/2, and LMP-2/7 genes in W-1s that could be elevated by pretreatment with IFN-γ to values equal to or greater than those expressed in EBV-PBLs. However, mRNA levels for the genes encoding MHC class II, Ii, CIITA, and DMA/B were markedly lower in both untreated and IFN-γ pretreated W-1s relative to EBV-PBLs. Furthermore, pulse-chase analysis of the corresponding genes revealed significantly lower protein levels and longer half-life expression in W-1s relative to EBV-PBLs. These results suggest that weak allogenicity of cardiac myocytes may be governed by their limited expression of MHC genes and gene products critical for antigen processing and presentation.

scholarly journals Cell Surface Expression of Major Histocompatibility Complex Class I Molecules Is Reduced in Hepatitis C Virus Subgenomic Replicon-Expressing Cells

2003 ◽  
Vol 77 (21) ◽  
pp. 11644-11650 ◽  
Author(s):  
Keith D. Tardif ◽  
Aleem Siddiqui
Keyword(s):  
Major Histocompatibility Complex ◽  
Hepatitis C ◽  
Cell Surface ◽  
Mhc Class I ◽  
Surface Expression ◽  
Protein Glycosylation ◽  
Class I ◽  
Cell Surface Expression ◽  
Histocompatibility Complex ◽  
Mhc Class I Molecules

ABSTRACT The hepatitis C virus (HCV) causes chronic hepatitis in most infected individuals by evading host immune defenses. In this investigation, we show that HCV-infected cells may go undetected in the immune system by suppressing major histocompatibility complex (MHC) class I antigen presentation to cytotoxic T lymphocytes. Cells expressing HCV subgenomic replicons have lower MHC class I cell surface expression. This is due to reduced levels of properly folded MHC class I molecules. HCV replicons induce endoplasmic reticulum (ER) stress (K. Tardif, K. Mori, and A. Siddiqui, J. Virol. 76:7453-7459, 2002), which results from a decline in protein glycosylation. Decreasing protein glycosylation can disrupt protein folding, preventing the assembly of MHC class I molecules. This results in the accumulation of unfolded MHC class I. Therefore, the persistence and pathogenesis of HCV may depend upon the ER stress-mediated interference of MHC class I assembly and cell surface expression.

scholarly journals The cationic region from HIV tat enhances the cell-surface expression of epitope/MHC class I complexes

Gene Therapy ◽  
2003 ◽  
Vol 10 (25) ◽  
pp. 2067-2073 ◽  
Author(s):  
J A Leifert ◽  
P D Holler ◽  
S Harkins ◽  
D M Kranz ◽  
J L Whitton
Keyword(s):  
Cell Surface ◽  
Mhc Class I ◽  
Surface Expression ◽  
Class I ◽  
Cell Surface Expression ◽  
Hiv Tat

scholarly journals E3/19K from adenovirus 2 is an immunosubversive protein that binds to a structural motif regulating the intracellular transport of major histocompatibility complex class I proteins.

1990 ◽  
Vol 172 (6) ◽  
pp. 1653-1664 ◽  
Author(s):  
W A Jefferies ◽  
H G Burgert
Keyword(s):  
Major Histocompatibility Complex ◽  
Cell Surface ◽  
Mhc Class I ◽  
Intracellular Transport ◽  
Surface Expression ◽  
Class I ◽  
Cell Surface Expression ◽  
Major Histocompatibility ◽  
Histocompatibility Complex ◽  
Mhc Class I Molecules

We have previously expressed in transgenic mice a chimeric H-2Kd/Kk protein called C31, which contains the extracellular alpha 1 domain of Kd, whereas the rest of the molecule is of Kk origin. This molecule functions as a restriction element for alloreactive and influenza A-specific cytotoxic T lymphocytes (CTL) but is only weakly expressed at the cell surface of splenocytes. Here, we show that the low cell surface expression is the result of slow intracellular transport and processing of the C31 protein. A set of hybrid molecules between Kd and Kk were used to localize the regions in major histocompatibility complex (MHC) molecules that are important for their intracellular transport and to further localize the structures responsible for binding to the adenovirus 2 E3/19K protein. This protein appears to be an important mediator of adenovirus persistence. It acts by binding to the immaturely glycosylated forms of MHC class I proteins in the endoplasmic reticulum (ER), preventing their passage to the cell surface and thereby reducing the recognition of infected cells by virus-specific T cells. We find the surprising result that intracellular transport and E3/19K binding are controlled primarily by the first half of the second domain of Kd, thus localizing these phenomena to the five polymorphic residues in this region of the Kd protein. This result implies that the E3/19K protein may act by inhibiting peptide binding or by disrupting the oligomerization of MHC class I molecules required for transport out of the ER. Alternatively, the E3/19K protein may inhibit the function of a positively acting transport molecule necessary for cell surface expression of MHC class I molecules.

scholarly journals Edmonston Measles Virus Prevents Increased Cell Surface Expression of Peptide-Loaded Major Histocompatibility Complex Class II Proteins in Human Peripheral Monocytes

2003 ◽  
Vol 77 (17) ◽  
pp. 9412-9421 ◽  
Author(s):  
Mamadi Yilla ◽  
Carole Hickman ◽  
Marcia McGrew ◽  
Elizabeth Meade ◽  
William J. Bellini
Keyword(s):  
Major Histocompatibility Complex ◽  
Protein Expression ◽  
Mhc Class Ii ◽  
Measles Virus ◽  
Surface Expression ◽  
Class Ii ◽  
Class I ◽  
Cell Surface Expression ◽  
Histocompatibility Complex ◽  
Ifn Γ

ABSTRACT Gamma interferon (IFN-γ) induces expression of the gene products of the major histocompatibility complex (MHC), whereas IFN-α/β can interfere with or suppress class II protein expression. In separate studies, measles virus (MV) was reported to induce IFN-α/β and to up-regulate MHC class II proteins. In an attempt to resolve this paradox, we examined the surface expression of MHC class I and class II proteins in MV-infected peripheral monocytes in the presence and absence of IFN-α/β. Infection of purified monocytes with Edmonston B MV resulted in an apparent increase in cell surface expression of HLA-A, -B, and -C class I proteins, but it had no effect on the expression of HLA-DR class II proteins. MV-infected purified monocytes expressed IFN-α/β, but no measurable IFN-γ expression was detected in supernatant fluids. Class II protein expression could be enhanced by coculture of purified monocytes with uninfected peripheral blood mononuclear cell (PBMC) supernatant. MV infection of PBMCs also did not affect expression of class II proteins, but the expression of HLA-A, -B, and -C class I proteins was increased two- to threefold in most donor cells. A direct role for IFN-α/β suppression of MHC class II protein expression was not evident in monocytes since MV suppressed class II protein expression in the absence of IFN-α/β. Taken together, these data suggest that MV interferes with the expression of peptide-loaded class II complexes, an effect that may potentially alter CD4+-T-cell proliferation and the cell-mediated immune responses that they help to regulate.

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