Tissue-specific factors differentially regulate the expression of antigen-processing enzymes during dendritic cell ontogeny
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PROVIDER: PRJNA603588 | ENA |
REPOSITORIES: ENA
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Project description:Dendritic cells (DC) form a collection of antigen-presenting cells that are distributed throughout the body. Conventional DC (cDC) which include the cDC1 and cDC2 subsets, and plasmacytoid DC (pDC) constitute the two major ontogenically distinct DC populations. The pDC complete their differentiation in bone-marrow (BM) while the cDC subsets derive from pre-committed bone-marrow (BM) precursors, the pre-cDC, that seed lymphoid and non-lymphoid tissues where they further differentiate into mature cDC1 and cDC2. Within different tissues, cDC express distinct phenotype and function. Notably cDC in the thymus are exquisitely efficient at processing and presenting antigens in the class II pathway, while in the spleen they do so only upon maturation induced by danger signals. To appraise this functional heterogeneity, we examined the regulation of the expression of distinct antigen-processing enzymes during DC ontogeny. We analyzed the expression of cathepsin S (CTSS), cathepsin L (CTSL) and thymus specific serine protease (TSSP), three major antigen-processing enzymes regulating class II presentation in cDC, by DC BM precursors and immature and mature cDC from spleen and thymus. We found that pre-cDC in the BM express relatively high levels of these different proteases. Then, their expression is modulated in a tissue-specific and subset–specific manner with immature and mature thymic cDC expressing overall higher levels than immature splenic cDC. On the other hand, TSSP expression level is selectively down-regulated in spleen pDC while CTSS and CTSL are both increased in thymic and splenic pDC. Hence tissue-specific factors program the expression levels of these different proteases during DC differentiation thus conferring tissue-specific function to the different DC subsets.
2020-01-29 | GSE144421 | GEO
Project description:Dendritic cells (DCs) form a collection of antigen-presenting cells (APCs) that are distributed throughout the body. Conventional DCs (cDCs), which include the cDC1 and cDC2 subsets, and plasmacytoid DCs (pDCs) constitute the two major ontogenically distinct DC populations. The pDCs complete their differentiation in the bone marrow (BM), whereas the cDC subsets derive from pre-committed BM precursors, the pre-cDC, that seed lymphoid and non-lymphoid tissues where they further differentiate into mature cDC1 and cDC2. Within different tissues, cDCs express distinct phenotype and function. Notably, cDCs in the thymus are exquisitely efficient at processing and presenting antigens in the class II pathway, whereas in the spleen they do so only upon maturation induced by danger signals. To appraise this functional heterogeneity, we examined the regulation of the expression of distinct antigen-processing enzymes during DC ontogeny. We analyzed the expression of cathepsin S (CTSS), cathepsin L (CTSL), and thymus-specific serine protease (TSSP), three major antigen-processing enzymes regulating class II presentation in cDC, by DC BM precursors and immature and mature cDCs from the spleen and thymus. We found that pre-cDCs in the BM express relatively high levels of these different proteases. Then, their expression is modulated in a tissue-specific and subset-specific manner with immature and mature thymic cDCs expressing overall higher levels than immature splenic cDCs. On the other hand, the TSSP expression level is selectively down-regulated in spleen pDCs, whereas CTSS and CTSL are both increased in thymic and splenic pDCs. Hence, tissue-specific factors program the expression levels of these different proteases during DC differentiation, thus conferring tissue-specific function to the different DC subsets.
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Project description:Primary Sjögren’s syndrome (pSS) is a systemic autoimmune disease characterized by lymphocytic infiltration of the exocrine glands. Conventional dendritic cells (cDCs)-2 play a critical role in T and B cell activation, leading to germinal centre formation and autoantibody production. To understand the mechanisms underlying cDC2 dysregulation in pSS we performed RNA-sequencing analysis and functional validation on circulating cDC2s from pSS, non-Sjögren’s sicca (nSS) patients and healthy controls (HC). Two independent cohorts were established to identify reproducible dysregulated signatures, which included the interferon (IFN), toll-like receptors (TLR) signaling and antigen processing and presentation pathways. We confirm by flow cytometry that pSS-cDC2s were less efficient to degrade BSA but more efficient to uptake BSA both linked with the presence of anti-SSA antibodies. As the majority of the SSA+ pSS patients exhibit an IFN-signature, we tested whether IFNα priming would influence cDC2s antigen-uptake and processing. IFNα priming increased cDC2s uptake capacity, but not antigen processing. Additionally, pSS-cDC2s showed an increased uptake capacity of apoptotic salivary gland epithelial cells. Finally, pSS-cDC2s increased the proliferation of HC CD4+ T cells and the expression of CXCR3 and CXCR5 on the proliferating HC CD4+ T cells, contributing to T cell migration into the inflamed salivary glands. Here we provide the first in-depth molecular characterization of pSS-cDC2s and show that the transcriptomic and functional alterations observed in pSS-cDC2s are linked to IFN-signature. In view of its role in pSS immunopathology, delineating the molecular networks that drive cDC2s holds promise for targeting these cells in pSS.
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Project description:Dendritic cells (DCs) process and present self and foreign antigens to induce tolerance or immunity. In vitro models suggest that induction of immunity is controlled by regulating the presentation of antigen, but little is known about how DCs control antigen presentation in vivo. To examine antigen processing and presentation in vivo we specifically targeted antigens to the two major subsets of DCs using chimeric monoclonal antibodies. Unlike CD8+ DCs that express the cell surface protein CD205, CD8- DCs, which are positive for the 33D1 antigen, are specialized for presentation on MHC class II. This difference in antigen processing is intrinsic to the DC subsets and associated with increased expression of proteins associated with MHC processing. Experiment Overall Design: This study includes data from cell sort purified dendritic cells, B cells and CD4 and CD8 T cells. The genearray was performed to identify the transmembrane molecule recognized by the antibody 33D1. The antibody 33D1 binds specifically to CD8-CD11cHigh DCs in the spleen. Therfore the data set was reduced in this way that all molecules that are expressed either in CD8=CD11cHigh DCs, B cells and T cells were diminished of the CD8+CD11cHigh DC data set. This Genearray was also used to analyze MHC class I and MHC class II associated moelcules as the DC subsets differ in the antigen presentation. Each Series consists of 3 individuall samples
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