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 The invariant chain is required for intracellular transport and function of major histocompatibility complex class II molecules.

1994 ◽  
Vol 179 (2) ◽  
pp. 681-694 ◽  
Author(s):  
E A Elliott ◽  
J R Drake ◽  
S Amigorena ◽  
J Elsemore ◽  
P Webster ◽  
...  
Keyword(s):  
Major Histocompatibility Complex ◽  
Mhc Class Ii ◽  
Intracellular Transport ◽  
Class Ii ◽  
Misfolded Proteins ◽  
Invariant Chain ◽  
Major Histocompatibility ◽  
Mhc Molecules ◽  
Histocompatibility Complex ◽  
And Function

The major histocompatibility complex (MHC) class II-associated invariant chain (Ii) is thought to act as a chaperone that assists class II during folding, assembly, and transport. To define more precisely the role of Ii chain in regulating class II function, we have investigated in detail the biosynthesis, transport, and intracellular distribution of class II molecules in splenocytes from mice bearing a deletion of the Ii gene. As observed previously, the absence of Ii chain caused significant reduction in both class II-restricted antigen presentation and expression of class II molecules at the cell surface because of the intracellular accumulation of alpha and beta chains. Whereas much of the newly synthesized MHC molecules enter a high molecular weight aggregate characteristic of misfolded proteins, most of the alpha and beta chains form dimers and acquire epitopes characteristic of properly folded complexes. Although the complexes do not bind endogenously processed peptides, class II molecules that reach the surface are competent to bind peptides added to the medium, further demonstrating that at least some of the complexes fold properly. Similar to misfolded proteins, however, the alpha and beta chains are poorly terminally glycosylated, suggesting that they fail to reach the Golgi complex. As demonstrated by double label confocal and electron microscope immunocytochemistry, class II molecules were found in a subcompartment of the endoplasmic reticulum and in a population of small nonlysosomal vesicles possibly corresponding to the intermediate compartment or cis-Golgi network. Thus, although alpha and beta chains can fold and form dimers on their own, the absence of Ii chain causes them to be recognized as "misfolded" and retained in the same compartments as bona fide misfolded proteins.

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 Survival of Mature CD4 T Lymphocytes Is Dependent on Major Histocompatibility Complex Class II–expressing Dendritic Cells

1997 ◽  
Vol 186 (8) ◽  
pp. 1223-1232 ◽  
Author(s):  
Thomas Brocker
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Major Histocompatibility Complex ◽  
T Cell ◽  
Mhc Class Ii ◽  
Cd4 T Cells ◽  
Close Contact ◽  
Class Ii ◽  
Major Histocompatibility ◽  
Histocompatibility Complex

Thymic T cell development is controlled by T cell receptor (TCR)–major histocompatibility complex (MHC) interactions, whereas a further dependence of peripheral mature T cells on TCR–MHC contact has not been described so far. To study this question, CD4 T cell survival was surveyed in mice lacking MHC class II expression and in mice expressing MHC class II exclusively on dendritic cells. Since neither of these mice positively select CD4 T cells in the thymus, they were grafted with MHC class II–positive embryonic thymic tissue, which had been depleted of bone marrow derived cells. Although the thymus grafts in both hosts were repopulated with host origin thymocytes of identical phenotype and numbers, an accumulation of CD4+ T cells in peripheral lymphoid organs could only be observed in mice expressing MHC class II on dendritic cells, but not in mice that were completely MHC class II deficient. As assessed by histology, the accumulating peripheral CD4 T cells were found to be in close contact with MHC class II+ dendritic cells, suggesting that CD4 T cells need peripheral MHC class II expression for survival and that class II+ dendritic cells might play an important role for the longevity of CD4 T cells.

scholarly journals Dynamic Tuning of T Cell Reactivity by Self-Peptide–Major Histocompatibility Complex Ligands

2001 ◽  
Vol 193 (10) ◽  
pp. 1179-1188 ◽  
Author(s):  
Phillip Wong ◽  
Gregory M. Barton ◽  
Katherine A. Forbush ◽  
Alexander Y. Rudensky
Keyword(s):  
Major Histocompatibility Complex ◽  
T Cell ◽  
Mhc Class Ii ◽  
T Cell Activation ◽  
Class Ii ◽  
Major Histocompatibility ◽  
Mhc Molecules ◽  
Dynamic Tuning ◽  
Endogenous Peptide ◽  
Histocompatibility Complex

Intrathymic self-peptide–major histocompatibility complex class II (MHC) molecules shape the T cell repertoire through positive and negative selection of immature CD4+CD8+ thymocytes. By analyzing the development of MHC class II–restricted T cell receptor (TCR) transgenic T cells under conditions in which the endogenous peptide repertoire is altered, we show that self-peptide–MHC complexes are also involved in setting T cell activation thresholds. This occurs through changes in the expression level of molecules on thymocytes that influence the sensitivity of TCR signaling. Our results suggest that the endogenous peptide repertoire modulates T cell responsiveness in the thymus in order to enforce tolerance to self-antigens.

scholarly journals Prevention of nephritis in major histocompatibility complex class II-deficient MRL-lpr mice.

1994 ◽  
Vol 179 (4) ◽  
pp. 1137-1143 ◽  
Author(s):  
A M Jevnikar ◽  
M J Grusby ◽  
L H Glimcher
Keyword(s):  
T Cells ◽  
Major Histocompatibility Complex ◽  
Mhc Class Ii ◽  
De Novo ◽  
Class Ii ◽  
Systemic Lupus Erythematosis ◽  
Major Histocompatibility ◽  
Mhc Molecules ◽  
Histocompatibility Complex

MRL-lpr mice develop aggressive autoimmune kidney disease associated with increased or de novo renal expression of major histocompatibility complex (MHC) class II molecules and a massive systemic expansion of CD4-CD- double negative (DN) T cells. Whereas non-MHC linked genes can have a profound effect on the development of nephritis, lymphadenopathy, and anti-DNA antibody production in MRL-lpr mice, the role of MHC molecules has not been unequivocally established. To study the role of MHC class II in this murine model of systemic lupus erythematosis, class II-deficient MRL-lpr mice (MRL-lpr -/-) were created. MRL-lpr -/- mice developed lymphadenopathy but not autoimmune renal disease or autoantibodies. This study demonstrates that class II expression is critical for the development of autoaggressive CD4+ T cells involved in autoimmune nephritis and clearly dissociates DN T cell expansion from autoimmune disease initiation.

scholarly journals H2-DMα−/− Mice Show the Importance of Major Histocompatibility Complex–Bound Peptide in Cardiac Allograft Rejection

2000 ◽  
Vol 192 (1) ◽  
pp. 31-40 ◽  
Author(s):  
Nathan J. Felix ◽  
W. June Brickey ◽  
Robert Griffiths ◽  
Jinghua Zhang ◽  
Luc Van Kaer ◽  
...  
Keyword(s):  
Major Histocompatibility Complex ◽  
T Cell ◽  
Mhc Class Ii ◽  
Class Ii ◽  
T Cell Response ◽  
Antigenic Peptides ◽  
Major Histocompatibility ◽  
Mhc Molecules ◽  
Histocompatibility Complex

The role played by antigenic peptides bound to major histocompatibility complex (MHC) molecules is evaluated with H2-DMα−/− mice. These mice have predominantly class II–associated invariant chain peptide (CLIP)-, not antigenic peptide–bound, MHC class II. H2-DMα−/− donor heart grafts survived three times longer than wild-type grafts and slightly longer than I-Aβb−/− grafts. Proliferative T cell response was absent, and cytolytic response was reduced against the H2-DMα−/− grafts in vivo. Residual cytolytic T cell and antibody responses against intact MHC class I lead to eventual rejection. Removal of both H2-DMα and β2-microglobulin (β2m) in cardiac grafts lead to greater (8–10 times) graft survival, whereas removal of β2m alone did not have any effect. These results demonstrate the significance of peptide rather than just allogeneic MHC, in eliciting graft rejection.

scholarly journals CD1 Molecules Efficiently Present Antigen in Immature Dendritic Cells and Traffic Independently of MHC Class II During Dendritic Cell Maturation

2002 ◽  
Vol 169 (9) ◽  
pp. 4770-4777 ◽  
Author(s):  
Xiaochun Cao ◽  
Masahiko Sugita ◽  
Nicole van der Wel ◽  
Jean Lai ◽  
Rick A. Rogers ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Dendritic Cell ◽  
Mhc Class Ii ◽  
Class Ii ◽  
Dendritic Cell Maturation ◽  
Cell Maturation ◽  
Immature Dendritic Cells

scholarly journals Targeted Expression of Major Histocompatibility Complex (MHC) Class II Molecules Demonstrates that Dendritic Cells Can Induce Negative but Not Positive Selection of Thymocytes In Vivo

1997 ◽  
Vol 185 (3) ◽  
pp. 541-550 ◽  
Author(s):  
Thomas Brocker ◽  
Mireille Riedinger ◽  
Klaus Karjalainen
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Major Histocompatibility Complex ◽  
Positive Selection ◽  
Mhc Class Ii ◽  
Class Ii ◽  
Major Histocompatibility ◽  
Histocompatibility Complex ◽  
Selection Of

It is well established that lymphoid dendritic cells (DC) play an important role in the immune system. Beside their role as potent inducers of primary T cell responses, DC seem to play a crucial part as major histocompatibility complex (MHC) class II+ “interdigitating cells” in the thymus during thymocyte development. Thymic DC have been implicated in tolerance induction and also by some authors in inducing major histocompatibility complex restriction of thymocytes. Most of our knowledge about thymic DC was obtained using highly invasive and manipulatory experimental protocols such as thymus reaggregation cultures, suspension cultures, thymus grafting, and bone marrow reconstitution experiments. The DC used in those studies had to go through extensive isolation procedures or were cultured with recombinant growth factors. Since the functions of DC after these in vitro manipulations have been reported to be not identical to those of DC in vivo, we intended to establish a system that would allow us to investigate DC function avoiding artificial interferences due to handling. Here we present a transgenic mouse model in which we targeted gene expression specifically to DC. Using the CD11c promoter we expressed MHC class II I-E molecules specifically on DC of all tissues, but not on other cell types. We report that I-E expression on thymic DC is sufficient to negatively select I-E reactive CD4+ T cells, and to a less complete extent, CD8+ T cells. In contrast, if only DC expressed I-E in a class II–deficient background, positive selection of CD4+ T cells could not be observed. Thus negative, but not positive, selection events can be induced by DC in vivo.

Sign in / Sign up

Export Citation Format

Share Document