Absence of MHC-II expression by lymph node stromal cells results in autoimmunity

Dubrot, Juan; Durães, Fernanda V.; Harlé, Guillaume; Schlaeppi, Anjalie; Brighouse, Dale; Madelon, Natacha; Göpfert, Christine; Stokar-Regenscheit, Nadine; Acha‐Orbea, Hans; Reith, Walter; Gannagé, Monique; Hugues, Stéphanie

doi:10.26508/lsa.201800164

Cited by 35 publications

(68 citation statements)

References 42 publications

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“…This promoter is responsive to IFNγ and other pro-inflammatory cytokines, which induce MHC II expression/up-regulation in fibroblasts and BEC (6). Similarly, in LEC it has been shown that endogenous MHC II expression is controlled by CIITA IV (4, 5). However, it is interesting to notice that, in contrast to other non-professional APC where pro-inflammatory stimuli greatly up-regulate surface MHC II molecules, pro-inflammatory stimuli induce less robust MHC II up-regulation in LEC (3, 5, 7).…”

Section: Mhc I and Mhc Ii Antigen Processing Machinerymentioning

confidence: 94%

“…The MHC II surface expression in LN-LEC is similar to what observed in BEC but less than fibroblastic reticular cells from LN (1). LEC MHC II molecules are both endogenously synthesized or acquired from hematopoietic cells, as determined by chimera experiments in MHC II −/− mice (1, 4, 5). At the transcription level, MHC II expression is regulated by CIITA, which is not a DNA binding factor but instead a transactivator that regulates quantitative aspects of MHC-II expression by binding the MHC-II enhanceosome (6).…”

Section: Mhc I and Mhc Ii Antigen Processing Machinerymentioning

confidence: 99%

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The Antigen Processing and Presentation Machinery in Lymphatic Endothelial Cells

2019

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Until a few years ago, lymphatic vessels and lymphatic endothelial cells (LEC) were viewed as part of a passive conduit for lymph and immune cells to reach lymph nodes (LN). However, recent work has shown that LEC are active immunological players whose interaction with dendritic cells and T cells is of important immunomodulatory relevance. While the immunological interaction between LEC and other immune cells has taken a center stage, molecular analysis of LEC antigen processing and presentation machinery is still lagging. Herein we review the current knowledge of LEC MHC I and MHC II antigen processing and presentation pathways, Including the role of LEC in antigen phagocytosis, classical, and non-classical MHC II presentation, proteasome processing and MHC I presentation, and cross-presentation. The ultimate goal is to provide an overview of the LEC antigen processing and presentation machinery that constitutes the molecular basis for their role in MHC I and MHC II-restricted immune responses.

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Section: Mhc I and Mhc Ii Antigen Processing Machinerymentioning

confidence: 94%

Section: Mhc I and Mhc Ii Antigen Processing Machinerymentioning

confidence: 99%

The Antigen Processing and Presentation Machinery in Lymphatic Endothelial Cells

2019

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“…Similarly, PD-L1 is upregulated in beta cells from humans with type 1 diabetes and NOD mice, in association with T cell infiltration and IFNγ production [34]. MHC-II expression on mouse LNSCs is low yet appears to be sufficient to affect autoreactive CD4 + T cells and contribute to the maintenance of regulatory T cells [35], and lack of MHC-II expression by LNSCs can result in autoimmunity in mice [36]. HLA-DR expression on human LNSCs is higher than in mice and, in the context of type 1 diabetes, was highly upregulated, along with PD-L1 to some extent.…”

Section: In S P T P R N G a D 2 G 6 P C 2 T Y R M L A N A T N F A Ipmentioning

confidence: 99%

Phenotypic alterations in pancreatic lymph node stromal cells from human donors with type 1 diabetes and NOD mice

2019

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Aims/hypothesis Tolerance induction in lymph nodes can be mediated by both haematopoietic cells (e.g. specific dendritic cells subsets) and by non-haematopoietic cells (e.g. lymph node stromal cells [LNSCs]) when they present peripheral tissue antigens to autoreactive T cells. LNSCs normally regulate T cell trafficking and survival and help to maintain peripheral tolerance by exerting immunosuppressive effects. However, whether autoimmunity can be associated with defective tolerogenic functions of LNSCs is unknown and studies aimed at characterising LNSCs in humans are lacking. We hypothesised that dysregulated T cell responses in pancreatic lymph nodes (PLNs) from donors with type 1 diabetes and from NOD mice may be associated with altered LNSC function. Methods We analysed PLNs from donors with type 1 diabetes and NOD mice for LNSC distribution and phenotype using flow cytometry. We assessed the expression of tolerance-related genes in different subsets of LNSCs from human donors, as well as in a population of dendritic cells enriched in autoimmune regulator (AIRE) + cells and identified as HLA-DR high CD45 low. Results The relative frequency of different LNSC subsets was altered in both donors with type 1 diabetes and NOD mice, and both MHC class II and programmed death-ligand 1 (PD-L1) expression were upregulated in human type 1 diabetes. Tolerancerelated genes showed similar expression profiles between mouse and human LNSCs at steady state but were generally upregulated in the context of human type 1 diabetes, while, at the same time, many such genes were downregulated in the AIREenriched dendritic cell population. Conclusion/interpretation Our study shows that LNSCs are substantially altered in type 1 diabetes, but, surprisingly, they exhibit an enhanced tolerogenic phenotype along with increased antigen-presenting potential, which may indicate an attempt to offset dendritic cell-related tolerogenic defects in tolerance. Thus, LNSCs could constitute alternative therapeutic targets in which to deliver antigens to help re-establish tolerance and prevent or treat type 1 diabetes. Data availability All data generated or analysed during this study are included in the published article (and its online supplementary files). Biomark gene expression data were deposited on the Mendeley repository at https://data.mendeley.com/datasets/ d9rdzdmvyf/1. Any other raw datasets are available from the corresponding author on reasonable request. No applicable resources were generated or analysed during the current study.

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“…In particular, LECs specifically induce CD4 + T cell death, whereas LECs, BECs and FRCs all induce T cell anergy (28). Moreover, our recent studies demonstrate that the loss of MHCII expression on LNSCs in murine LNs impairs peripheral CD4 + T cell tolerance, and alters regulatory T cell populations, resulting in signs of spontaneous autoimmunity in elderly (30). Their lack of costimulatory molecules could explain LNSC implication in T cell tolerance.…”

Section: Lymphatic Vessels As Immunoregulators In Non-tumor Contextmentioning

confidence: 99%

Tumor-Associated Lymphatic Vessel Features and Immunomodulatory Functions

2019

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The lymphatic system comprises a network of lymphoid tissues and vessels that drains the extracellular compartment of most tissues. During tumor development, lymphatic endothelial cells (LECs) substantially expand in response to VEGFR-3 engagement by VEGF-C produced in the tumor microenvironment, a process known as tumor-associated lymphangiogenesis. Lymphatic drainage from the tumor to the draining lymph nodes consequently increases, powering interstitial flow in the tumor stroma. The ability of a tumor to induce and activate lymphatic growth has been positively correlated with metastasis. Much effort has been made to identify genes responsible for tumor-associated lymphangiogenesis. Inhibition of lymphangiogenesis with soluble VEGFR-3 or with specific monoclonal antibodies decreases tumor spread to LNs in rodent models. Importantly, tumor-associated lymphatics do not only operate as tumor cell transporters but also play critical roles in anti-tumor immunity. Therefore, metastatic as well as primary tumor progression can be affected by manipulating tumor-associated lymphatic remodeling or function. Here, we review and discuss our current knowledge on the contribution of LECs immersed in the tumor microenvironment as immunoregulators, as well as a possible functional remodeling of LECs subsets depending on the organ microenvironment.

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Absence of MHC-II expression by lymph node stromal cells results in autoimmunity

Abstract: MHCII-restricted antigen presentation by lymph node stromal cells is essential for regulatory T-cell proliferation and functions, and for the regulation of autoimmunity.

Cited by 35 publications

References 42 publications

The Antigen Processing and Presentation Machinery in Lymphatic Endothelial Cells

The Antigen Processing and Presentation Machinery in Lymphatic Endothelial Cells

Phenotypic alterations in pancreatic lymph node stromal cells from human donors with type 1 diabetes and NOD mice

Tumor-Associated Lymphatic Vessel Features and Immunomodulatory Functions

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