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 Relationship between invariant chain expression and major histocompatibility complex class II transport into early and late endocytic compartments.

1993 ◽  
Vol 177 (3) ◽  
pp. 583-596 ◽  
Author(s):  
P Romagnoli ◽  
C Layet ◽  
J Yewdell ◽  
O Bakke ◽  
R N Germain
Keyword(s):  
Major Histocompatibility Complex ◽  
Mhc Class Ii ◽  
Class Ii ◽  
Endocytic Pathway ◽  
Invariant Chain ◽  
Major Histocompatibility ◽  
Histocompatibility Complex ◽  
Late Endosomes ◽  
Early Endosomes ◽  
Endocytic Compartments

Invariant chain (Ii), which associates with major histocompatibility complex (MHC) class II molecules in the endoplasmic reticulum, contains a targeting signal for transport to intracellular vesicles in the endocytic pathway. The characteristics of the target vesicles and the relationship between Ii structure and class II localization in distinct endosomal subcompartments have not been well defined. We demonstrate here that in transiently transfected COS cells expressing high levels of the p31 or p41 forms of Ii, uncleaved Ii is transported to and accumulates in transferrin-accessible (early) endosomes. Coexpressed MHC class II is also found in this same compartment. These early endosomes show altered morphology and a slower rate of content movement to later parts of the endocytic pathway. At more moderate levels of Ii expression, or after removal of a highly conserved region in the cytoplasmic tail of Ii, coexpressed class II molecules are found primarily in vesicles with the characteristics of late endosomes/prelysosomes. The Ii chains in these late endocytic vesicles have undergone proteolytic cleavage in the lumenal region postulated to control MHC class II peptide binding. These data indicate that the association of class II with Ii results in initial movement to early endosomes. At high levels of Ii expression, egress to later endocytic compartments is delayed and class II-Ii complexes accumulate together with endocytosed material. At lower levels of Ii expression, class II-Ii complexes are found primarily in late endosomes/prelysosomes. These data provide evidence that the route of class II transport to the site of antigen processing and loading involves movement through early endosomes to late endosomes/prelysosomes. Our results also reveal an unexpected ability of intact Ii to modify the structure and function of the early endosomal compartment, which may play a role in regulating this processing pathway.

scholarly journals CD1 and Major Histocompatibility Complex II Molecules Follow a Different Course during Dendritic Cell Maturation

2003 ◽  
Vol 14 (8) ◽  
pp. 3378-3388 ◽  
Author(s):  
Nicole N. van der Wel ◽  
Masahiko Sugita ◽  
Donna M. Fluitsma ◽  
Xaiochun Cao ◽  
Gerty Schreibelt ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Major Histocompatibility Complex ◽  
Dendritic Cell ◽  
Mhc Class Ii ◽  
Class Ii ◽  
Dendritic Cell Maturation ◽  
Cell Maturation ◽  
Major Histocompatibility ◽  
Mhc Molecules ◽  
Histocompatibility Complex

The maturation of dendritic cells is accompanied by the redistribution of major histocompatibility complex (MHC) class II molecules from the lysosomal MHC class II compartment to the plasma membrane to mediate presentation of peptide antigens. Besides MHC molecules, dendritic cells also express CD1 molecules that mediate presentation of lipid antigens. Herein, we show that in human monocyte-derived dendritic cells, unlike MHC class II, the steady-state distribution of lysosomal CD1b and CD1c isoforms was unperturbed in response to lipopolysaccharide-induced maturation. However, the lysosomes in these cells underwent a dramatic reorganization into electron dense tubules with altered lysosomal protein composition. These structures matured into novel and morphologically unique compartments, here termed mature dendritic cell lysosomes (MDL). Furthermore, we show that upon activation mature dendritic cells do not lose their ability of efficient clathrin-mediated endocytosis as demonstrated for CD1b and transferrin receptor molecules. Thus, the constitutive endocytosis of CD1b molecules and the differential sorting of MHC class II from lysosomes separate peptide- and lipid antigen-presenting molecules during dendritic cell maturation.

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 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

2001 ◽  
Vol 69 (4) ◽  
pp. 2407-2415 ◽  
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.

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

1997 ◽  
Vol 139 (3) ◽  
pp. 639-649 ◽  
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.

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.

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