scholarly journals Human Cytomegalovirus Inhibits Major Histocompatibility Complex Class II Expression By Disruption of the Jak/Stat Pathway

1998 ◽  
Vol 187 (5) ◽  
pp. 675-683 ◽  
Author(s):  
Daniel M. Miller ◽  
Brian M. Rahill ◽  
Jeremy M. Boss ◽  
Michael D. Lairmore ◽  
Joan E. Durbin ◽  
...  
Keyword(s):  
Signal Transduction ◽  
Mhc Class Ii ◽  
Human Cytomegalovirus ◽  
Laboratory Strain ◽  
Class Ii ◽  
Interferon Γ ◽  
Janus Kinase ◽  
Mobility Shift ◽  
Ifn Γ ◽  
Stat Pathway

Human cytomegalovirus (HCMV) is a ubiquitous herpesvirus that is able to persist for decades in its host. HCMV has evolved protean countermeasures for anti-HCMV cellular immunity that facilitate establishment of persistence. Recently it has been shown that HCMV inhibits interferon γ (IFN-γ)–stimulated MHC class II expression, but the mechanism for this effect is unknown. IFN-γ signal transduction (Jak/Stat pathway) and class II transactivator (CIITA) are required components for IFN-γ–stimulated MHC class II expression. In this study, we demonstrate that both a clinical isolate and a laboratory strain of HCMV inhibit inducible MHC class II expression at the cell surface and at RNA level in human endothelial cells and fibroblasts. Moreover, reverse transcriptase polymerase chain reaction and Northern blot analyses demonstrate that neither CIITA nor interferon regulatory factor 1 are upregulated in infected cells. Electrophoretic mobility shift assays reveal a defect in IFN-γ signal transduction, which was shown by immunoprecipitation to be associated with a striking decrease in Janus kinase 1 (Jak1) levels. Proteasome inhibitor studies with carboxybenzyl-leucyl-leucyl-leucine vinyl sulfone suggest an HCMV-associated enhancement of Jak1 protein degradation. This is the first report of a mechanism for the HCMV-mediated disruption of inducible MHC class II expression and a direct virus-associated alteration in Janus kinase levels. These findings are yet another example of the diverse mechanisms by which HCMV avoids immunosurveillance and establishes persistence.

scholarly journals IL-6-mediated MHC class II induction on RIN-5AH insulinoma cells by IFN-γ occurs via the G-protein pathway

1995 ◽  
Vol 4 (5) ◽  
pp. 374-379 ◽  
Author(s):  
S. Vassiliadis ◽  
G. K. Papadopoulos
Keyword(s):  
Signal Transduction ◽  
Type 1 Diabetes ◽  
G Protein ◽  
Mhc Class Ii ◽  
Antigen Expression ◽  
Class Ii ◽  
Ifn Γ ◽  
Class Ii Antigen ◽  
Mhc Class Ii Antigen

Major histocompatibility complex (MHC) class II antigen expression has been implicated in the pathogenesis of autoimmune type 1 diabetes. In this study we examined the role of various cytoldnes that may induce MHC class II surface antigen expression, using the rat insulinoma line RIN-5AH as a pertinent model system. As in another study, the ability of IFN-γ to amplify MHC class II antigen expression 4-fold is demonstrated. At the same time we noted a 5-fold increase of these histocompatibility antigens by IL-6. Signal transduction analysis reveals that IL-6-induced MHC class II expression is specifically mediated by the G-protein system (activation of p21rasby IL-6) since mevalonic acid lactone (a Gprotein inhibitor) abolishes the action of IL-6. In contrast, IFN-γ, which does not activate p21ras, is not inhibited by protein kinase C (PKC) inhibitors but by those of the G-protein pathway. This finding raises the possibility that IFN-γ induces RIN cells to secrete IL-6 (as shown previously, as well as in this paper) which, in turn, increases class II antigen expression via the G-protein pathway. This action may be unique to IL-6 or in synergy with IFN-γ. Other cytokines such as IL-1α and β, and TNF-α induce a smaller increase in MHC class II antigens on RIN cells, and appear to activate both the G-protein and the PKC signal transduction pathways to varying degrees. Therefore, injury of pancreatic β-cells and possible induction of autoimmune type 1 diabetes via various cytokines may be caused by IL-6 or IFN-γ, or by their ability to induce MHC class II antigen upregulation.

scholarly journals Identification of a transcription factor that binds to the S box of the I-A β gene of the major histocompatibility complex

1996 ◽  
Vol 313 (3) ◽  
pp. 737-744 ◽  
Author(s):  
Antonio CELADA ◽  
Pilar GIL ◽  
Scott R. McKERCHER ◽  
Richard A. MAKI
Keyword(s):  
Binding Site ◽  
Mhc Class Ii ◽  
Class Ii ◽  
Interferon Γ ◽  
Affinity Column ◽  
Nuclear Factor ◽  
Conserved Sequence ◽  
Histocompatibility Complex ◽  
Dnase I Footprinting ◽  
Ifn Γ

Class II genes of the MHC show a striking homology upstream of the transcription start site that is composed of three conserved sequences (S, X and Y boxes, each separated by 15–20 bp). The presence of the S-box sequence in the mouse MHC class II gene I-Aβ was examined for its influence on the expression of this gene. Deletion or mutation of the S box decreased the induction of chloramphenicol acetyltransferase (CAT) activity in B lymphocytes by 32%. In macrophages, deletion or mutation of the S box abolished interferon-γ (IFN-γ) inducibility of CAT activity. Using a gel-retardation assay, we have identified a nuclear factor whose binding site overlaps the 7-mer conserved sequence of the S box. This factor is present in lymphocytes, macrophages, mastocytes and fibroblasts. Surprisingly, binding of this nuclear factor to DNA was induced by IFN-γ in bone-marrow-derived macrophages, but not in macrophage-like cell lines. The binding site for this factor was defined by DNase I footprinting and partially purified by using an affinity column containing double-stranded oligonucleotides containing a sequence of the S box. A prominent protein of 43 kDa was found that bound specifically to the S-box sequence.

scholarly journals CIITA G-286A promoter polymorphism impairs monocytes HLA-DR expression in septic shock and is rescued by interferon-γ

2021 ◽  
Author(s):  
Jordi Miatello ◽  
Anne-Claire Lukaszewicz ◽  
Valérie Faivre ◽  
Stéphane Hua ◽  
Kim Zita Martinet ◽  
...  
Keyword(s):  
Septic Shock ◽  
Mhc Class Ii ◽  
Promoter Activity ◽  
Class Ii ◽  
Interferon Γ ◽  
Site Directed Mutagenesis ◽  
Proximal Promoter ◽  
List Type ◽  
Hla Dr ◽  
Ifn Γ

ABSTRACTMonocyte HLA-DR is an increasingly recognized markers of sepsis-induced immunodepression, but its regulatory mechanisms remain poorly understood in sepsis. Several evidence for positive selection on the 5’ promoter region of HLA class II transactivator (CIITA) gene, the master regulator of MHC class II, have been gathered in the European population, and its role in sepsis has never been demonstrated, whilst suggested in autoimmune disease. We aim to describe the effect of rs3087456 polymorphism, localized on CIITA promoter III (pIII), on mortality of patients with septic shock, and investigate the mechanisms regulating HLA-DR expression. Genotyping of 203 patients with septic shock showed that, in A dominant model, GG genotype was associated with 28-day mortality (OR 2.29; 95%CI: 1.01 to 5.22; P = 0.043). Monocyte HLA-DR remained low in patients with GG genotype whereas it increases as early as at the end of the first week in intensive care in patients with AA or AG genotype. Using site-directed mutagenesis, in vitro reporter gene promoter activity of the pIII was decreased in GG genotype in monocyte cell line. Interferon-γ (IFN-γ) restored pIII activity in GG genotype as well as restore, in ex vivo experiment in healthy volunteers, CIITA pIII expression of GG genotype. Hereby, we demonstrated that rs3087456, a positively selected polymorphism of CIITA proximal promoter, significantly impact monocyte HLA-DR expression in patients with septic shock through CIITA promoter activity, that can be rescued using IFN-γ, offering a new perspective in genetic susceptibility to sepsis and targeted immunomodulatory therapy.KeypointsCIITA G-286A polymorphism reduces promotor activity and significantly impact monocyte HLA-DR expression and mortality in septic shockDownregulatory effects of CIITA G-286A polymorphism on monocyte HLA-DR expression can be reverse by IFN-γ in patients with septic shock

scholarly journals Nontoxic Shiga Toxin Derivatives from Escherichia coli Possess Adjuvant Activity for the Augmentation of Antigen-Specific Immune Responses via Dendritic Cell Activation

2005 ◽  
Vol 73 (7) ◽  
pp. 4088-4097 ◽  
Author(s):  
Mari Ohmura ◽  
Masafumi Yamamoto ◽  
Chikako Tomiyama-Miyaji ◽  
Yoshikazu Yuki ◽  
Yoshifumi Takeda ◽  
...  
Keyword(s):  
T Cell ◽  
Mhc Class Ii ◽  
Shiga Toxin ◽  
Cell Activation ◽  
Class Ii ◽  
Immunoglobulin M ◽  
Interleukin 12 ◽  
Adjuvant Activity ◽  
Ifn Γ ◽  
Th1 And Th2

ABSTRACT Shiga toxin (Stx) derivatives, such as the Stx1 B subunit (StxB1), which mediates toxin binding to the membrane, and mutant Stx1 (mStx1), which is a nontoxic doubly mutated Stx1 harboring amino acid substitutions in the A subunit, possess adjuvant activity via the activation of dendritic cells (DCs). Our results showed that StxB1 and mStx1, but not native Stx1 (nStx1), resulted in enhanced expression of CD86, CD40, and major histocompatibility complex (MHC) class II molecules and, to some extent, also enhanced the expression of CD80 on bone marrow-derived DCs. StxB1-treated DCs exhibited an increase in tumor necrosis factor alpha and interleukin-12 (IL-12) production, a stimulation of DO11.10 T-cell proliferation, and the production of both Th1 and Th2 cytokines, including gamma interferon (IFN-γ), IL-4, IL-5, IL-6, and IL-10. When mice were given StxB1 subcutaneously, the levels of CD80, CD86, and CD40, as well as MHC class II expression by splenic DCs, were enhanced. The subcutaneous immunization of mice with ovalbumin (OVA) plus mStx1 or StxB1 induced high titers of OVA-specific immunoglobulin M (IgM), IgG1, and IgG2a in serum. OVA-specific CD4+ T cells isolated from mice immunized with OVA plus mStx1 or StxB1 produced IFN-γ, IL-4, IL-5, IL-6, and IL-10, indicating that mStx1 and StxB1 elicit both Th1- and Th2-type responses. Importantly, mice immunized subcutaneously with tetanus toxoid plus mStx1 or StxB1 were protected from a lethal challenge with tetanus toxin. These results suggest that nontoxic Stx derivatives, including both StxB1 and mStx1, could be effective adjuvants for the induction of mixed Th-type CD4+ T-cell-mediated antigen-specific antibody responses via the activation of DCs.

scholarly journals Modulation of Major Histocompatibility Class II Protein Expression by Varicella-Zoster Virus

2000 ◽  
Vol 74 (4) ◽  
pp. 1900-1907 ◽  
Author(s):  
Allison Abendroth ◽  
Barry Slobedman ◽  
Eunice Lee ◽  
Elizabeth Mellins ◽  
Mark Wallace ◽  
...  
Keyword(s):  
Cell Surface ◽  
Varicella Zoster Virus ◽  
Mhc Class Ii ◽  
Class Ii ◽  
Northern Blot Hybridization ◽  
Major Histocompatibility ◽  
Varicella Zoster ◽  
Ifn Γ ◽  
In Cells

ABSTRACT We sought to investigate the effects of varicella-zoster virus (VZV) infection on gamma interferon (IFN-γ)-stimulated expression of cell surface major histocompatibility complex (MHC) class II molecules on human fibroblasts. IFN-γ treatment induced cell surface MHC class II expression on 60 to 86% of uninfected cells, compared to 20 to 30% of cells which had been infected with VZV prior to the addition of IFN-γ. In contrast, cells that were treated with IFN-γ before VZV infection had profiles of MHC class II expression similar to those of uninfected cell populations. Neither IFN-γ treatment nor VZV infection affected the expression of transferrin receptor (CD71). In situ and Northern blot hybridization of MHC II (MHC class II DR-α) RNA expression in response to IFN-γ stimulation revealed that MHC class II DR-α mRNA accumulated in uninfected cells but not in cells infected with VZV. When skin biopsies of varicella lesions were analyzed by in situ hybridization, MHC class II transcripts were detected in areas around lesions but not in cells that were infected with VZV. VZV infection inhibited the expression of Stat 1α and Jak2 proteins but had little effect on Jak1. Analysis of regulatory events in the IFN-γ signaling pathway showed that VZV infection inhibited transcription of interferon regulatory factor 1 and the MHC class II transactivator. This is the first report that VZV encodes an immunomodulatory function which directly interferes with the IFN-γ signal transduction via the Jak/Stat pathway and enables the virus to inhibit IFN-γ induction of cell surface MHC class II expression. This inhibition of MHC class II expression on VZV-infected cells in vivo may transiently protect cells from CD4+ T-cell immune surveillance, facilitating local virus replication and transmission during the first few days of cutaneous lesion formation.

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