Allotransplantation of culture-isolated neonatal rat islet tissue. Absence of MHC class II positive antigen-presenting cells in nonimmunogenic islets

The composition and location of professional antigen presenting cells (APC) varies in different mucosal surfaces. The cornea, long considered an immune-privileged tissue devoid of APCs, is now known to host a heterogeneous network of bone marrow-derived cells. Here, we utilized transgenic mice that express enhanced green fluorescent protein (EGFP) from the CD 11c promoter (pCD11c) in conjunction with immunohistochemical staining to demonstrate an interesting stratification of APCs within non-inflamed murine corneas. pCD11c+ dendritic cells (DCs) reside in the basal epithelium, seemingly embedded in the basement membrane. Most DCs express MHC class II on at least some dendrites, which extend up to 50 μm in length and traverse up 20 μm tangentially towards the apical surface of the epithelium. The DC density diminishes from peripheral to central cornea. Beneath the DCs and adjacent to the stromal side of the basement membrane reside pCD11c–CD11b+ putative macrophages that express low levels of MHC class II. Finally, MHC class II–pCD11c–CD11b+ cells form a network throughout the remainder of the stroma. This highly reproducible stratification of bone marrow-derived cells is suggestive of a progression from an APC function at the exposed corneal surface to an innate immune barrier function deeper in the stroma.

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HLA-DMA and -DMB genes are both required for MHC class II/peptide complex formation in antigen-presenting cells

Nature ◽

10.1038/368554a0 ◽

1994 ◽

Vol 368 (6471) ◽

pp. 554-558 ◽

Cited By ~ 193

Author(s):

Steven P. Fling ◽

Benjamin Arp ◽

Donald Pious

Keyword(s):

Complex Formation ◽

Mhc Class Ii ◽

Antigen Presenting Cells ◽

Class Ii ◽

Peptide Complex ◽

Antigen Presenting

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Endocytosis and Biosynthetic Transport of Murine MHC Class II Molecules in Antigen Presenting Cells

Endocytosis ◽

10.1007/978-3-642-84295-5_42 ◽

1992 ◽

pp. 341-342

Author(s):

J. Davoust ◽

P. Cosson ◽

J. M. Escola ◽

J. Henry ◽

M. Humbert ◽

...

Keyword(s):

Mhc Class Ii ◽

Antigen Presenting Cells ◽

Class Ii ◽

Antigen Presenting ◽

Mhc Class Ii Molecules

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Quantitative Analysis of the Efficiency of Clonal Deletion in the Thymus

Developmental Immunology ◽

10.1155/1994/92025 ◽

1994 ◽

Vol 4 (1) ◽

pp. 43-53 ◽

Cited By ~ 10

Author(s):

Lisa M. Spain ◽

Leslie J. Berg

Keyword(s):

Epithelial Cells ◽

Mhc Class Ii ◽

Negative Selection ◽

Gene Dosage ◽

Antigen Presenting Cells ◽

Class Ii ◽

Clonal Deletion ◽

Self Tolerance ◽

Antigen Presenting ◽

Mhc Class Ii Molecules

One of the major mechanisms for establishing self-tolerance is the clonal deletion of self-reactive T cells during their development in the thymus. Using a TCR transgenic mouse model, we have established a quantitativeex vivoassay for examining the sensitivity and specificity of negative selection. Thymic organ cultures established from mice of varying MHC haplotypes were incubated with antigen, and the efficiency of clonal deletion assessed. We show here that clonal deletion of CD4+8+thymocytes is sensitive to both the gene dosage and the allelic variation of MHC class II molecules expressed on thymic antigen-presenting cells. We also find that when epithelial cells in the thymic cortex are the only antigen-presenting cells expressing the appropriate MHC class II molecules, negative selection of CD4+8+cells is as efficient as when antigen is presented on all thymic antigen-presenting cells. These studies demonstrate that the induction of self-tolerance via clonal deletion in the thymus is a function not only of antigen concentration, but also of MHC class II cell-surface density. In addition, together with the reports of others, these results confirm that cortical epithelial cells can mediate negative selection, and demonstrate that they do so in the intact thymic microenvironment.

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Expression of intercellular adhesion molecule 1 (ICAM-1) on the human oviductal epithelium and mediation of lymphoid cell adherence

Reproduction ◽

10.1530/reprod/120.1.115 ◽

2000 ◽

pp. 115-123 ◽

Cited By ~ 9

Author(s):

E Utreras ◽

P Ossandon ◽

C Acuna-Castillo ◽

L Varela-Nallar ◽

C Muller ◽

...

Keyword(s):

Mhc Class Ii ◽

Adhesion Molecule ◽

Antigen Presenting Cells ◽

Class Ii ◽

Intercellular Adhesion ◽

Intercellular Adhesion Molecule ◽

Intercellular Adhesion Molecule 1 ◽

Oviductal Epithelium ◽

Antigen Presenting ◽

Human Oviduct

The epithelium of the human oviduct expresses the major histocompatibility complex (MHC) class II and shows endocytic properties towards luminal antigens. Therefore, the epithelial cells might behave as antigen-presenting cells, inducing a local immune response. The activation of antigen-specific T cells not only requires presentation of the peptide antigen by MHC class II, but also the presence of co-stimulatory molecules in the antigen-presenting cells. Therefore, the expression of the intercellular adhesion molecule 1 (ICAM-1) was examined in the epithelium of the human oviduct. Most oviducts showed epithelial ICAM-1 expression, as assessed by immunocytochemistry, western blot analysis and RT-PCR assay, and the expression was restricted to the luminal border of ciliated and secretory cells. Interferon gamma, interleukin 1 and lipopolysaccharide treatments increased the percentage of ICAM-1-positive cells in primary cultures, indicating that the expression of ICAM-1 in the oviduct might be upregulated in vivo by inflammatory cytokines or bacterial infections. Binding assays between allogenic phytohaemagglutinin-activated lymphocytes and epithelial monolayers expressing ICAM-1 demonstrated that this molecule stimulated lymphocyte adherence. The presence of ICAM-1, in addition to MHC class II, supports the putative role of the oviductal epithelium in antigen presentation. The exclusive apical distribution of ICAM-1 indicates that T-cell activation would occur in a polarized manner. Binding of lymphoid cells to the surface of the oviductal epithelium may help to retain these immune cells that are required for the clearance of pathogens.

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C-Type Lectin Receptor Mediated Immune Recognition of ADAMTS13 Promotes HLA-DRB1*11 Dependent Presentation of CUB1-2 Derived Peptides by Dendritic Cells

Blood ◽

10.1182/blood.v118.21.196.196 ◽

2011 ◽

Vol 118 (21) ◽

pp. 196-196

Author(s):

Nicoletta Sorvillo ◽

Simon D van Haren ◽

Wouter Pos ◽

Eszter Herczenik ◽

Rob Fijnheer ◽

...

Keyword(s):

T Cells ◽

Dendritic Cells ◽

Mhc Class Ii ◽

Cd4 T Cells ◽

Antigen Presenting Cells ◽

Class Ii ◽

Immune Recognition ◽

Dependent Manner ◽

Sirna Silencing ◽

Antigen Presenting

Abstract Abstract 196 ADAMTS13 is a plasma metalloproteinase that regulates platelet adhesion and aggregation by virtue of its ability to process newly released ultra-large von Willebrand factor (VWF) multimers on the surface of endothelial cells. Autoantibodies directed against ADAMTS13 prohibit the processing of VWF multimers initiating a rare and life-threatening disorder called acquired thrombotic thrombocytopenic purpura (TTP). HLA-DRB1*11 has recently been identified as a risk factor for acquired TTP. This finding implies that formation of autoantibodies towards ADAMTS13 depends on appropriate presentation of ADAMTS13 derived peptides to CD4+ T-cells by antigen presenting cells. Here, we investigate endocytosis of recombinant ADAMTS13 by immature monocyte-derived dendritic cells (iDCs) using flow cytometry and confocal microscopy. Upon incubation of fluorescently labeled-rADAMTS13 with DCs, a time- and concentration dependent uptake of ADAMTS13 was observed. Endocytosis of ADAMTS13 was completely blocked upon addition of EGTA and mannan. We subsequently explored involvement of C-type lectins (CLRs) in the uptake of ADAMTS13 using specific blocking antibodies and siRNA silencing. We found that ADAMTS13 endocytosis was significantly decreased in cells treated with a monoclonal antibody directed towards macrophage mannose receptor (MR). Furthermore siRNA silencing of MR reduced the uptake of ADAMTS13 by dendritic cells. In vitro binding studies revealed that ADAMTS13 interacts with the carbohydrate recognition domains of MR. These data show that ADAMTS13 is internalized by iDCs in a MR-dependent manner. Antigen presenting cells continuously process endogenous and exogenous antigens into small peptides that are loaded on MHC class I or MHC class II for presentation to T lymphocytes. We have recently developed a method to analyze HLA-DR-presented peptide repertoires of dendritic cells pulsed with antigen (van Haren et al., 2011). Here, we addressed which ADAMTS13-derived peptides were presented on MHC class II alleles of a panel of both HLA-DRB1*11 positive and negative donors. Compared to previous studies with model antigens only a limited number of ADAMTS13-derived peptides were presented on MHC class II. Inspection of peptide-profiles obtained from DRB1*11 positive individuals revealed that two antigenic “core” peptides derived from the CUB1-2 domains of ADAMTS13 were presented by a DR11-positive donor. In addition to these immuno-dominant peptides several other peptides were also presented although with a markedly reduced efficiency. Our findings show that DRB1*11 expressing antigen presenting cells preferentially present antigenic “core” peptides derived from the CUB1-2 domains of ADAMTS13. We hypothesize that functional presentation of these peptides on HLA-DRB1*11 contributes to the onset of acquired TTP by stimulating low affinity self-reactive CD4+ T cells that have escaped negative selection in the thymus. Disclosures: No relevant conflicts of interest to declare.

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