scholarly journals Engagement of major histocompatibility complex class II molecules by superantigen induces inflammatory cytokine gene expression in human rheumatoid fibroblast-like synoviocytes.

1992 ◽  
Vol 175 (2) ◽  
pp. 613-616 ◽  
Author(s):  
W Mourad ◽  
K Mehindate ◽  
T J Schall ◽  
S R McColl
Keyword(s):  
Gene Expression ◽  
Major Histocompatibility Complex ◽  
Mhc Class Ii ◽  
Inflammatory Cytokine ◽  
Class Ii ◽  
Type B ◽  
Major Histocompatibility ◽  
Ifn Gamma ◽  
Histocompatibility Complex ◽  
Mhc Class Ii Molecules

Cells in the rheumatoid synovium express high levels of major histocompatibility complex (MHC) class II molecules in vivo. We have therefore examined the ability of engagement of MHC class II molecules by the superantigen Staphylococcal enterotoxin A (SEA) to activate interleukin 6 (IL-6) and IL-8 gene expression in type B synoviocytes isolated from patients with rheumatoid arthritis. SEA had a minimal or undetectable effect on the expression of either gene in resting synoviocytes, as determined by Northern blot and specific enzyme-linked immunosorbent assay. However, induction of MHC class II molecule expression after treatment of synoviocytes with interferon gamma (IFN-gamma) enabled the cells to respond to SEA in a dose-dependent manner, resulting in an increase in both the level of steady-state mRNA for IL-6 and IL-8, and the release of these cytokines into the supernatant. IFN-gamma by itself had no effect on the expression of either cytokine. Pretreatment of the cells with the transcription inhibitor actinomycin D prevented the increase in cytokine mRNA induced by SEA, whereas cycloheximide superinduced mRNA for both cytokines after stimulation by SEA. Taken together, these results indicate that signaling through MHC class II molecules may represent a novel mechanism by which inflammatory cytokine production is regulated in type B rheumatoid synoviocytes, and potentially provides insight into the manner by which superantigens may initiate and/or propagate autoimmune diseases.

scholarly journals Major histocompatibility complex-restricted recognition of retroviral superantigens by V beta 17+ T cells.

1992 ◽  
Vol 176 (1) ◽  
pp. 275-280 ◽  
Author(s):  
M A Blackman ◽  
F E Lund ◽  
S Surman ◽  
R B Corley ◽  
D L Woodland
Keyword(s):  
T Cells ◽  
Major Histocompatibility Complex ◽  
Mhc Class Ii ◽  
Class Ii ◽  
Major Histocompatibility ◽  
Direct Role ◽  
Histocompatibility Complex ◽  
Class Ii Mhc ◽  
Mhc Class Ii Molecules

It has been established that at least some V beta 17+ T cells interact with an endogenous superantigen encoded by the murine retrovirus, Mtv-9. To analyze the role of major histocompatibility complex (MHC) class II molecules in presenting the Mtv-9 encoded superantigen, vSAG-9 to V beta 17+ hybridomas, a panel of nine hybridomas was tested for their ability to respond to A20/2J (H-2d) and LBK (H-2a) cells which had been transfected with the vSAG-9 gene. Whereas some of the hybridomas recognized vSAG-9 exclusively in the context of H-2a, other hybridomas recognized vSAG-9 exclusively in the context of H-2d or in the context of both H-2d and H-2a. These results suggest that: (a) the class II MHC molecule plays a direct role in the recognition of retroviral superantigen by T cells, rather than serving simply as a platform for presentation; and, (b) it is likely that components of the TCR other than V beta are involved in the vSAG-9/TCR/class II interaction.

scholarly journals Species-specific binding of CD4 to the beta 2 domain of major histocompatibility complex class II molecules.

1992 ◽  
Vol 175 (4) ◽  
pp. 925-932 ◽  
Author(s):  
D A Vignali ◽  
J Moreno ◽  
D Schiller ◽  
G J Hämmerling
Keyword(s):  
Major Histocompatibility Complex ◽  
Mhc Class Ii ◽  
Peptide Binding ◽  
Class Ii ◽  
Major Histocompatibility ◽  
Species Barrier ◽  
Interaction Sites ◽  
Histocompatibility Complex ◽  
Beta 2 ◽  
Mhc Class Ii Molecules

Exon-shuffled constructs between mouse (IA beta b) and human (DR3 beta) class II beta chains were made to study the interaction sites between CD4 and major histocompatibility complex (MHC) class II molecules, and to determine whether a species barrier is involved. The overall structure and the peptide binding groove appeared to be unaffected by the exon shuffling procedure as determined by monoclonal antibody and peptide binding assays, respectively. While purified CD4+ BALB/c T cells responded strongly in a mixed leukocyte reaction to transfectants expressing the whole IA molecule, the response to IA molecules containing a DR beta 2 domain was substantially reduced. In addition, the presence of an IA beta 2 domain in DR failed to restore the weak xenoreactivity to the whole DR molecule. Similar observations were made with murine HEL-specific, IA alpha k beta b-restricted T cell hybridomas which responded significantly stronger to the whole compared with the exon-shuffled IA molecules. The involvement of CD4 in these differential responses was confirmed by the observation that CD4 loss variants responded to both molecules comparably, and transfection of CD4 into these cells restored the parental phenotype. In contrast, CD4 loss variants transfected with human CD4 responded equally to both the whole and the exon-shuffled molecules. Taken together, these data imply the existence of a partial species barrier, and suggest that CD4 interacts with the beta 2 domain of MHC class II molecules, probably in addition to other contact sites. Models for the interaction of CD4 with MHC class II molecules are presented.

scholarly journals Interferon (IFN) beta acts downstream of IFN-gamma-induced class II transactivator messenger RNA accumulation to block major histocompatibility complex class II gene expression and requires the 48-kD DNA-binding protein, ISGF3-gamma.

1995 ◽  
Vol 182 (5) ◽  
pp. 1517-1525 ◽  
Author(s):  
H T Lu ◽  
J L Riley ◽  
G T Babcock ◽  
M Huston ◽  
G R Stark ◽  
...  
Keyword(s):  
Major Histocompatibility Complex ◽  
Mhc Class Ii ◽  
Messenger Rna ◽  
Class Ii ◽  
Type I ◽  
Major Histocompatibility ◽  
Mrna Accumulation ◽  
Class Ii Transactivator ◽  
Ifn Gamma ◽  
Histocompatibility Complex

Interferon (IFN) gamma, a cardinal proinflammatory cytokine, induces expression of the gene products of the class II locus of the major histocompatibility complex (MHC), whereas IFN-alpha or -beta suppresses MHC class II expression. The mechanism of IFN-beta-mediated MHC class II inhibition has been unclear. Recently, a novel factor termed class II transactivator (CIITA) has been identified as essential for IFN-gamma-induced MHC class II transcription. We studied the status of IFN-gamma-induced CIITA messenger RNA (mRNA) accumulation and CIITA-driven transactivation in IFN-beta-treated cells and used cell lines that had defined defects in the type I IFN response pathway to address the roles of IFN signaling components in the inhibition of MHC class II induction. IFN-beta treatment did not suppress IFN-gamma-induced accumulation of CIITA mRNA. After cells were stably transfected with CIITA, endogenous MHC class II genes were constitutively expressed, and MHC class II promoters, delivered by transfection, were actively transcribed in CIITA-expressing cells. Expression of these promoters was significantly impaired by pretreatment with IFN-beta. These results suggest that IFN-beta acts downstream of CIITA mRNA accumulation, and acts in part by reducing the functional competence of CIITA for transactivating MHC class II promoters. IFN stimulated gene factor 3 (ISGF3) gamma was essential for IFN-beta to mediate inhibition of MHC class II induction, regardless of whether MHC class II transcription was stimulated by IFN-gamma or directly by CIITA expression. Results of these experiments suggest that inhibition of MHC class II in IFN-beta-treated cells requires expression of gene(s) directed by the ISGF3-IFN-stimulated response element pathway, and that these gene product(s) may act by blocking CIITA-driven transcription of MHC class II promoters.

scholarly journals Distinct Intracellular Compartments Involved in Invariant Chain Degradation and Antigenic Peptide Loading of Major Histocompatibility Complex (MHC) Class II Molecules

1997 ◽  
Vol 139 (6) ◽  
pp. 1433-1446 ◽  
Author(s):  
Giorgio Ferrari ◽  
Andrew M. Knight ◽  
Colin Watts ◽  
Jean Pieters
Keyword(s):  
Major Histocompatibility Complex ◽  
Mhc Class Ii ◽  
Human Leukocyte ◽  
Subcellular Location ◽  
Class Ii ◽  
Invariant Chain ◽  
Major Histocompatibility ◽  
Histocompatibility Complex ◽  
Peptide Loading ◽  
Mhc Class Ii Molecules

Major histocompatibility complex (MHC) class II molecules are transported to intracellular MHC class II compartments via a transient association with the invariant chain (Ii). After removal of the invariant chain, peptides can be loaded onto class II molecules, a process catalyzed by human leukocyte antigen-DM (HLA-DM) molecules. Here we show that MHC class II compartments consist of two physically and functionally distinct organelles. Newly synthesized MHC class II/Ii complexes were targeted to endocytic organelles lacking HLA-DM molecules, where Ii degradation occurred. From these organelles, class II molecules were transported to a distinct organelle containing HLA-DM, in which peptides were loaded onto class II molecules. This latter organelle was not directly accessible via fluid phase endocytosis, suggesting that it is not part of the endosomal pathway. Uptake via antigen-specific membrane immunoglobulin resulted however in small amounts of antigen in the HLA-DM positive organelles. From this peptide-loading compartment, class II–peptide complexes were transported to the plasma membrane, in part after transit through endocytic organelles. The existence of two separate compartments, one involved in Ii removal and the other functioning in HLA-DM–dependent peptide loading of class II molecules, may contribute to the efficiency of antigen presentation by the selective recruitment of peptide-receptive MHC class II molecules and HLA-DM to the same subcellular location.

scholarly journals Binding sites for bacterial and endogenous retroviral superantigens can be dissociated on major histocompatibility complex class II molecules.

1994 ◽  
Vol 179 (3) ◽  
pp. 1029-1034 ◽  
Author(s):  
J Thibodeau ◽  
N Labrecque ◽  
F Denis ◽  
B T Huber ◽  
R P Sékaly
Keyword(s):  
T Cells ◽  
Major Histocompatibility Complex ◽  
Mhc Class Ii ◽  
Binding Sites ◽  
Cell Receptor ◽  
Class Ii ◽  
Bacterial Toxins ◽  
Major Histocompatibility ◽  
Histocompatibility Complex ◽  
Mhc Class Ii Molecules

Bacterial and retroviral superantigens (SAGs) interact with major histocompatibility complex (MHC) class II molecules and stimulate T cells upon binding to the V beta portion of the T cell receptor. Whereas both types of molecules exert similar effects on T cells, they have very different primary structures. Amino acids critical for the binding of bacterial toxins to class II molecules have been identified but little is known of the molecular interactions between class II and retroviral SAGs. To determine whether both types of superantigens interact with the same regions of MHC class II molecules, we have generated mutant HLA-DR molecules which have lost the capacity to bind three bacterial toxins (Staphylococcus aureus enterotoxin A [SEA], S. aureus enterotoxin B [SEB], and toxic shock syndrome toxin 1 [TSST-1]). Cells expressing these mutated class II molecules efficiently presented two retroviral SAGs (Mtv-9 and Mtv-7) to T cells while they were unable to present the bacterial SAGs. These results demonstrate that the binding sites for both types of SAGs can be dissociated.

scholarly journals Major histocompatibility complex class II-restricted presentation of an internally synthesized antigen displays cell-type variability and segregates from the exogenous class II and endogenous class I presentation pathways.

1993 ◽  
Vol 178 (1) ◽  
pp. 73-85 ◽  
Author(s):  
G E Loss ◽  
C G Elias ◽  
P E Fields ◽  
R K Ribaudo ◽  
M McKisic ◽  
...  
Keyword(s):  
Major Histocompatibility Complex ◽  
Mhc Class Ii ◽  
Transmembrane Protein ◽  
Class Ii ◽  
Class I ◽  
Major Histocompatibility ◽  
Membrane Expression ◽  
Histocompatibility Complex ◽  
Presentation Pathway ◽  
Mhc Class Ii Molecules

Although reported examples of endogenous antigen (Ag) presentation by major histocompatibility complex (MHC) class II molecules have increased, the mechanisms governing this process remain poorly defined. In this communication, we describe an experimental system designed to examine the mechanisms governing class II presentation of internal Ag. Our target peptide is processed from a transmembrane protein constitutively expressed by a variety of nucleated cells (MHC class I, H-2Ld), is naturally displayed by MHC class II molecules in vivo, and is recognized by a class II-restricted, CD4+ T cell hybridoma. Our results indicate that presentation of the Ld target Ag is independent of its plasma membrane expression, may not involve endosomal proteolysis, and thus may be distinct from the classically defined class II presentation pathway. In addition, the observations that Ld presentation does not require a functional TAP-1 complex, is not blocked by invariant chain, and cannot utilize cytoplasmic forms of H-2Ld, suggest that a classical class I pathway is not involved in this presentation event. Finally, our data suggest that different cofactors participate in MHC class II presentation of exogenous and endogenous Ag, and that disparate Ag presenting cells, such as B, T, and pancreatic islet cells, may differentially express these two class II pathways of Ag presentation.

scholarly journals Two DNA-binding proteins discriminate between the promoters of different members of the major histocompatibility complex class II multigene family

1990 ◽  
Vol 10 (3) ◽  
pp. 965-971
Author(s):  
M Kobr ◽  
W Reith ◽  
C Herrero-Sanchez ◽  
B Mach
Keyword(s):  
Gene Expression ◽  
Major Histocompatibility Complex ◽  
Mhc Class Ii ◽  
Dna Sequences ◽  
Multigene Family ◽  
Class Ii ◽  
Major Histocompatibility ◽  
Histocompatibility Complex ◽  
Hla Dr ◽  
Beta Chain Genes

The regulation of major histocompatibility complex (MHC) class II gene expression is a key feature of the control of normal and abnormal immune responses. In humans, class II alpha - and beta-chain genes are organized in a multigene family with three distinct subregions, HLA-DR, -DQ, and -DP. The regulation of these genes is generally coordinated, and their promoters contain highly conserved motifs, in particular the X and Y boxes. We have identified five distinct proteins that bind to specific DNA sequences within the first 145 base pairs of the HLA-DR promoter, a segment known to be functionally essential for class II gene regulation. Among these, RF-X is of special interest, since mutants affected in the regulation of MHC class II gene expression have a specific defect in RF-X binding. Unexpectedly, RF-X displays a characteristic gradient of binding affinities for the X boxes of three alpha-chain genes (DRA greater than DPA much greater than DQA). The same observation was made with recombinant RF-X. We also describe a novel factor, NF-S, which bound to the spacer region between the X and Y boxes of class II promoters. NF-S exhibited a reverse gradient of affinity compared with RF-X (DQA greater than DPA much greater than DRA). As expected, RF-X bound well to the mouse IE alpha promoter, while NF-S bound well to IA alpha. The drastic differences in the binding of RF-X and NF-S to different MHC class II promoters contrasts with the coordinate regulation of HLA-DR, -DQ, and -DP genes.

scholarly journals The Formation of Immunogenic Major Histocompatibility Complex Class II–Peptide Ligands in Lysosomal Compartments of Dendritic Cells Is Regulated by Inflammatory Stimuli

2000 ◽  
Vol 191 (6) ◽  
pp. 927-936 ◽  
Author(s):  
Kayo Inaba ◽  
Shannon Turley ◽  
Tomonori Iyoda ◽  
Fumiya Yamaide ◽  
Susumu Shimoyama ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Major Histocompatibility Complex ◽  
Mhc Class Ii ◽  
Class Ii ◽  
Major Histocompatibility ◽  
Histocompatibility Complex ◽  
Late Endosomes ◽  
Inflammatory Stimuli ◽  
Peptide Complexes ◽  
Mhc Class Ii Molecules

During their final differentiation or maturation, dendritic cells (DCs) redistribute their major histocompatibility complex (MHC) class II products from intracellular compartments to the plasma membrane. Using cells arrested in the immature state, we now find that DCs also regulate the initial intracellular formation of immunogenic MHC class II–peptide complexes. Immature DCs internalize the protein antigen, hen egg lysozyme (HEL), into late endosomes and lysosomes rich in MHC class II molecules. There, despite extensive colocalization of HEL protein and MHC class II products, MHC class II–peptide complexes do not form unless the DCs are exposed to inflammatory mediators such as tumor necrosis factor α, CD40 ligand, or lipoplolysaccharide. The control of T cell receptor (TCR) ligand formation was observed using the C4H3 monoclonal antibody to detect MHC class II–HEL peptide complexes by flow cytometry and confocal microscopy, and with HEL-specific 3A9 transgenic T cells to detect downregulation of the TCR upon MHC–peptide encounter. Even the binding of preprocessed HEL peptide to MHC class II is blocked in immature DCs, including the formation of C4H3 epitope in MHC class II compartments, suggesting an arrest to antigen presentation at the peptide-loading step, rather than an enhanced degradation of MHC class II–peptide complexes at the cell surface, as described in previous work. Therefore, the capacity of late endosomes and lysosomes to produce MHC class II–peptide complexes can be strictly controlled during DC differentiation, helping to coordinate antigen acquisition and inflammatory stimuli with formation of TCR ligands. The increased ability of maturing DCs to load MHC class II molecules with antigenic cargo contributes to the >100-fold enhancement of the subsequent primary immune response observed when immature and mature DCs are compared as immune adjuvants in culture and in mice.

scholarly journals Developmental extinction of major histocompatibility complex class II gene expression in plasmocytes is mediated by silencing of the transactivator gene CIITA.

1994 ◽  
Vol 180 (4) ◽  
pp. 1329-1336 ◽  
Author(s):  
P Silacci ◽  
A Mottet ◽  
V Steimle ◽  
W Reith ◽  
B Mach
Keyword(s):  
Gene Expression ◽  
Major Histocompatibility Complex ◽  
B Lymphocytes ◽  
Mhc Class Ii ◽  
Plasma Cells ◽  
Terminal Differentiation ◽  
Class Ii ◽  
Major Histocompatibility ◽  
Histocompatibility Complex ◽  
Mhc Class Ii Genes

Constitutive major histocompatibility complex (MHC) class II gene expression is tightly restricted to antigen presenting cells and is under developmental control. Cells of the B cell lineage acquire the capacity to express MHC class II genes early during ontogeny and lose this property during terminal differentiation into plasma cells. Cell fusion experiments have suggested that the extinction of MHC class II expression in plasma cells is due to a dominant repression, but the underlying mechanisms are not understood. CIITA was recently identified as an MHC class II transactivator that is essential for MHC class II expression in B lymphocytes. We show here that inactivation of MHC class II genes in plasmocytes is associated with silencing of the CIITA gene. Moreover, experimentally induced expression of CIITA in plasmocytes leads to reexpression of MHC class II molecules to the same level as that observed on B lymphocytes. We therefore conclude that the loss of MHC class II expression observed upon terminal differentiation of B lymphocytes into plasmocytes results from silencing of the transactivator gene CIITA.

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