Antigen-B Cell Receptor Complexes Associate with Intracellular major histocompatibility complex (MHC) Class II Molecules

Antigen recognition by clonotypic B cell receptor (BcR) is the first step of B lymphocytes differentiation into plasmocytes. This B cell function is dependent on efficient major histocompatibility complex (MHC) class II–restricted presentation of BcR-bound antigens. In this work, we analyzed the subcellular mechanisms underlying antigen presentation after BcR engagement on B cells. In quiescent B cells, we found that MHC class II molecules mostly accumulated at the cell surface and in an intracellular pool of tubulovesicular structures, whereas H2-M molecules were mostly detected in distinct lysosomal compartments devoid of MHC class II. BcR stimulation induced the transient intracellular accumulation of MHC class II molecules in newly formed multivesicular bodies (MVBs), to which H2-M was recruited. The reversible downregulation of cathepsin S activity led to the transient accumulation of invariant chain–MHC class II complexes in MVBs. A few hours after BcR engagement, cathepsin S activity increased, the p10 invariant chain disappeared, and MHC class II–peptide complexes arrived at the plasma membrane. Thus, BcR engagement induced the transient formation of antigen-processing compartments, enabling antigen-specific B cells to become effective antigen-presenting cells.

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

Journal of Experimental Medicine ◽

10.1084/jem.179.3.1029 ◽

1994 ◽

Vol 179 (3) ◽

pp. 1029-1034 ◽

Cited By ~ 26

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.

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Faculty Opinions recommendation of B cell receptor ligation induces display of V-region peptides on MHC class II molecules to T cells.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.737033557.793568970 ◽

2019 ◽

Author(s):

Jim Drake

Keyword(s):

T Cells ◽

B Cell ◽

Mhc Class Ii ◽

Cell Receptor ◽

Class Ii ◽

B Cell Receptor ◽

V Region ◽

Receptor Ligation ◽

Mhc Class Ii Molecules

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

Journal of Experimental Medicine ◽

10.1084/jem.175.2.613 ◽

1992 ◽

Vol 175 (2) ◽

pp. 613-616 ◽

Cited By ~ 64

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.

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

Journal of Experimental Medicine ◽

10.1084/jem.176.1.275 ◽

1992 ◽

Vol 176 (1) ◽

pp. 275-280 ◽

Cited By ~ 15

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.

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Deficient Major Histocompatibility Complex Class II Antigen Presentation in a Subset of Hodgkin's Disease Tumor Cells

Blood ◽

10.1182/blood.v92.7.2252 ◽

1998 ◽

Vol 92 (7) ◽

pp. 2252-2259 ◽

Cited By ~ 25

Author(s):

Herbert Bosshart ◽

Ruth F. Jarrett

Keyword(s):

Major Histocompatibility Complex ◽

Antigen Presentation ◽

Tumor Cells ◽

Mhc Class Ii ◽

Hodgkin's Disease ◽

Hodgkin’S Disease ◽

Class Ii ◽

Histocompatibility Complex ◽

Class Ii Antigen ◽

Mhc Class Ii Molecules

Abstract Hodgkin's disease is a common malignancy of the lymphoid system. Although the scarce Hodgkin and Reed-Sternberg (HRS) tumor cells in involved tissue synthesize major histocompatibility complex (MHC) class II and costimulatory molecules such as CD40 or CD86, it is unclear whether these tumor cells are operational antigen-presenting cells (APC). We developed an immunofluorescence-based assay to determine the number of MHC class II molecules present on the surface of single living HRS cells. We found that in fresh Hodgkin's disease lymph node biopsies, a subset of HRS cells express a substantial number of surface MHC class II molecules that are occupied by MHC class II–associated invariant chain peptides (CLIP), indicating deficient loading of MHC class II molecules with antigenic peptides. Cultured Hodgkin's disease–derived (HD) cell lines, however, were found to express few MHC class II molecules carrying CLIP peptides on the cell surface and were shown to generate sodium dodecyl sulphate (SDS)-stable MHC class II αβ dimers. In addition to showing deficient MHC class II antigen presentation in a subset of HRS cells, our results show that the widely used HD-cell lines are not ideal in vitro models for the disease. The disruption of MHC class II–restricted antigen presentation in HRS cells could represent a key mechanism by which these tumor cells escape immune surveillance.

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Major Histocompatibility Complex Class II-Independent Generation of Neutralizing Antibodies against T-Cell-Dependent Borrelia burgdorferi Antigens Presented by Dendritic Cells: Regulation by NK and γδ T Cells

Infection and Immunity ◽

10.1128/iai.69.4.2407-2415.2001 ◽

2001 ◽

Vol 69 (4) ◽

pp. 2407-2415 ◽

Cited By ~ 11

Author(s):

M. Lamine Mbow ◽

Nordin Zeidner ◽

Robert D. Gilmore ◽

Marc Dolan ◽

Joseph Piesman ◽

...

Keyword(s):

T Cells ◽

Dendritic Cells ◽

Major Histocompatibility Complex ◽

Borrelia Burgdorferi ◽

Mhc Class Ii ◽

Γδ T Cells ◽

Humoral Response ◽

Class Ii ◽

Histocompatibility Complex ◽

Mhc Class Ii Molecules

ABSTRACT We previously showed that adoptive transfer of Borrelia burgdorferi-pulsed dendritic cells (DCs) into syngeneic mice protects animals from challenge with tick-transmitted spirochetes. Here, we demonstrate that the protective immune response is antibody (Ab) dependent and does not require the presence of major histocompatibility complex (MHC) class II molecules on DCs. Mice sensitized with B. burgdorferi-pulsed MHC class II-deficient (MHC class II−/−) DCs mounted a humoral response against protective antigens, includingB. burgdorferi outer surface protein A (OspA) and OspC. B-cell help for the generation of neutralizing anti-OspC immunoglobulin G Abs could be provided by γδ T cells. In contrast, anti-OspA Ab production required the presence of αβ T cells, although this pathway could be independent of MHC class II molecules on antigen-presenting cells. Moreover, depletion of NK cells prior to transfer of antigen-pulsed MHC class II−/− DCs resulted in significant increases in the levels of neutralizing Abs induced by DCs. Altogether, these data suggest that the initial interactions between DCs and innate immune cells, such as γδ and NK cells, can influence the generation of a protective humoral response againstB. burgdorferi antigens.

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

Journal of Experimental Medicine ◽

10.1084/jem.175.4.925 ◽

1992 ◽

Vol 175 (4) ◽

pp. 925-932 ◽

Cited By ~ 39

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.

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Major Histocompatibility Complex Class II Compartments in Human and Mouse B Lymphoblasts Represent Conventional Endocytic Compartments

The Journal of Cell Biology ◽

10.1083/jcb.139.3.639 ◽

1997 ◽

Vol 139 (3) ◽

pp. 639-649 ◽

Cited By ~ 157

Author(s):

Monique J. Kleijmeer ◽

Stanislaw Morkowski ◽

Janice M. Griffith ◽

Alexander Y. Rudensky ◽

Hans J. Geuze

Keyword(s):

Major Histocompatibility Complex ◽

B Cells ◽

Mhc Class Ii ◽

Class Ii ◽

Invariant Chain ◽

Histocompatibility Complex ◽

Peptide Complexes ◽

Endocytic Compartments ◽

Human And Mouse ◽

Mhc Class Ii Molecules

In most human and mouse antigen-presenting cells, the majority of intracellular major histocompatibility complex (MHC) class II molecules resides in late endocytic MHC class II compartments (MIICs), thought to function in antigen processing and peptide loading. However, in mouse A20 B cells, early endocytic class II-containing vesicles (CIIVs) have been reported to contain most of the intracellular MHC class II molecules and have also been implicated in formation of MHC class II–peptide complexes. To address this discrepancy, we have studied in great detail the endocytic pathways of both a human (6H5.DM) and a mouse (A20.Ab) B cell line. Using quantitative immunoelectron microscopy on cryosections of cells that had been pulse–chased with transferrin-HRP or BSA-gold as endocytic tracers, we have identified up to six endocytic subcompartments including an early MIIC type enriched in invariant chain, suggesting that it serves as an important entrance to the endocytic pathway for newly synthesized MHC class II/invariant chain complexes. In addition, early MIICs represented the earliest endocytic compartment containing MHC class II– peptide complexes, as shown by using an antibody against an abundant endogenous class II–peptide complex. The early MIIC exhibited several though not all of the characteristics reported for the CIIV and was situated just downstream of early endosomes. We have not encountered any special class II-containing endocytic structures besides those normally present in nonantigen-presenting cells. Our results therefore suggest that B cells use conventional endocytic compartments rather than having developed a unique compartment to accomplish MHC class II presentation.

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