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MHCII mediated Antigen-presentation by Lymph Node Stromal Cells in Autoimmunity and Cancer

English title MHCII mediated Antigen-presentation by Lymph Node Stromal Cells in Autoimmunity and Cancer
Applicant Hugues Stéphanie
Number 166541
Funding scheme Project funding
Research institution Département de Pathologie et Immunologie Faculté de Médecine / CMU Université de Genève
Institution of higher education University of Geneva - GE
Main discipline Immunology, Immunopathology
Start/End 01.09.2016 - 31.08.2019
Approved amount 678'000.00
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All Disciplines (2)

Discipline
Immunology, Immunopathology
Cellular Biology, Cytology

Keywords (8)

mouse models; antigen-presentation; lymph node stromal cells; fibroblatic reticular cells; T lymphocyte; lymphatic endothelial cells; autoimmunity; cancers

Lay Summary (French)

Lead
Impact de la présentation de antigènes par les cellules stromales des ganglions lymphatiques sur la réponse des lymphocytes T dans le développpement de maladies autoimmunes et de cancers.
Lay summary

Notre système immunitaire possède des mécanismes permettant d’éliminer les pathogènes  tout en restant « neutre » vis à vis de nos propres tissus. Cette dernière fonction est appelée tolérance immune vis à vis du soi. Cependant, des lymphocytes T reconnaissant le soi circulent dans nos organes lymphoides secondaires, pouvant entrainer le développement de maladies autoimmunes. Des mécanismes d’inhibition des ces lymphocytes T autoréactifs existent afin de maintenir la tolérance vis à vis du soi. Lors du développement de cancers, les cellules tumorales produisent des facteurs visant à inhiber la réponse des lymphocytes T anti-tumoraux. Ceci mime un état de tolérance vis à vis des tumeurs, qu’il serait intéressant de renverser, afin de promouvoir une immunité anti-tumorale plus efficace.

Les cellules dendritiques (CD) sont spécialisées dans la présentation d’antigènes dérivés de pathogènes aux lymphocytes T afin d’initier la réponse T contre un pathogène. Elles sont également importantes dans la présentation des antigènes du soi et l’inactivation des lymphocytes T autoréactifs. Récemment, d’autres cellules résidant dans les organes lymphoides secondaires, les cellules stromales, à l’origine considérées comme des piliers architecturaux des organes lymphoides secondaires, ont également été décrites pour être impliquées dans la tolérance. Nous étudions leur rôle dans l’inactivation des lymphocytes T autoréactifs d’une part, et dans celle des lymphocytes T anti-tumoraux, d’autre part. Le but étant d’identifier des cibles spécifiques de ces cellules afin de respectivement favoriser, ou inhiber, cette fonction d’inactivation de la réponse des lymphocytes T.

Le projet relève de la recherche fondamentale, et utilise des souris génétiquement modifiées permettent d’abolir spécifiquement une fonction particulière d’un type cellulaire, et d’analyser les conséquences sur la réponse des lymphocytes T, dans des modèle murins de maladies autoimmunes et de cancers.
Direct link to Lay Summary Last update: 29.04.2016

Responsible applicant and co-applicants

Employees

Publications

Publication
Tumor-Associated Lymphatic Vessel Features and Immunomodulatory Functions
Garnier Laure, Gkountidi Anastasia-Olga, Hugues Stephanie (2019), Tumor-Associated Lymphatic Vessel Features and Immunomodulatory Functions, in Frontiers in Immunology, 10, 720.
Absence of MHC-II expression by lymph node stromal cells results in autoimmunity
Dubrot Juan, Duraes Fernanda V, Harlé Guillaume, Schlaeppi Anjalie, Brighouse Dale, Madelon Natacha, Göpfert Christine, Stokar-Regenscheit Nadine, Acha-Orbea Hans, Reith Walter, Gannagé Monique, Hugues Stephanie (2018), Absence of MHC-II expression by lymph node stromal cells results in autoimmunity, in Life Science Alliance, 1(6), e201800164-e201800164.
Extended Freeze-Dried BCG Instructed pDCs Induce Suppressive Tregs and Dampen EAE
Lippens Carla, Garnier Laure, Guyonvarc'h Pierre-Marie, Santiago-Raber Marie-Laure, Hugues Stéphanie (2018), Extended Freeze-Dried BCG Instructed pDCs Induce Suppressive Tregs and Dampen EAE, in Frontiers in Immunology, 9, 2777.
Warming up the tumor microenvironment in order to enhance immunogenicity
Humbert Marion, Hugues Stephanie (2018), Warming up the tumor microenvironment in order to enhance immunogenicity, in OncoImmunology, 8(1), e1510710-e1510710.
Intratumoral CpG-B Promotes Antitumoral Neutrophil, cDC, and T-cell Cooperation without Reprograming Tolerogenic pDC
Humbert Marion, Hugues Stephanie (2018), Intratumoral CpG-B Promotes Antitumoral Neutrophil, cDC, and T-cell Cooperation without Reprograming Tolerogenic pDC, in Cancer Research, 2549.
Shaping of Peripheral T Cell Responses by Lymphatic Endothelial Cells
Humbert Marion, Hugues Stéphanie, Dubrot Juan (2017), Shaping of Peripheral T Cell Responses by Lymphatic Endothelial Cells, in Frontiers in Immunology, 7, 684.
IDO-orchestrated crosstalk between pDCs and Tregs inhibits autoimmunity
Lippens Carla, Duraes Fernanda V., Dubrot Juan, Brighouse Dale, Lacroix Mathilde, Irla Magali, Aubry-Lachainaye Jean-Pierre, Reith Walter, Mandl Judith N., Hugues Stéphanie (2016), IDO-orchestrated crosstalk between pDCs and Tregs inhibits autoimmunity, in Journal of Autoimmunity, 75, 39-49.

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
SAI ANNUAL CONGRESS 2019 Talk given at a conference invited speaker 05.09.2019 Lugano, Switzerland Hugues Stéphanie;
EMBO antigen processing and presentation workshop Talk given at a conference invited speaker 15.04.2019 Paris, France Gkountidi Olga-Anastasia; Hugues Stéphanie;


Associated projects

Number Title Start Funding scheme
152951 The study of how plasmacytoid dendritic cells can be manipulated to control inflammatory and autoimmune diseases 01.09.2014 SNSF Professorships
185255 Role of lymphatic endothelial cells in Autoimmunity and Cancer 01.09.2019 Project funding
185255 Role of lymphatic endothelial cells in Autoimmunity and Cancer 01.09.2019 Project funding

Abstract

Lymph node (LN) stromal cells (LNSCs) are essential to the structure and function of the LN. LNSC functions include the generation of a tissue scaffold for the support of hematopoietic cells, the release of chemoattractants that facilitate migration and interactions between hematopoietic cells, and homeostasis of immune cells. Recently, LNSCs, and in particular two subtypes, the fibroblastic reticular cells (FRCs) and lymphatic endothelial cells (LECs), have been shown to express antigens (Ags) otherwise restricted to a small number of peripheral tissues. Direct presentation of peripheral tissue Ags (PTA) by LECs and FRCs to CD8+ T cells results in their abortive proliferation and deletion. These findings suggest that LN-LECs and LN-FRCs perform functions in the periphery similar to that of medullary thymic epithelial cells (mTECs) to promote T cell tolerance. We have recently demonstrated that LECs and FRCs acquire peptide-MHCII complexes from dendritic cells (DCs), and present them to CD4+ T cells to induce T cell dysfunction. Additionally, LEC and FRC show significant levels of endogenous MHCII, especially under inflammatory conditions. However, whether LEC and FRC Ag presentation through endogenous MHCII molecules has an impact on CD4+ T cells responses remains unknown. Our preliminary data suggest that the selective loss of MHCII expression on LNSCs in murine LN impairs peripheral CD4+ T cell tolerance and alters regulatory T cell (Treg) populations, resulting in signs of spontaneous autoimmunity in elderly. The aims 1 and 2 of this proposal will determine how LECs and/or FRCs contribute to MHCII-mediated self-reactive CD4+ T cell inactivation, and identify the mechanisms accounting for T cell tolerance maintenance. In aim 1, we plan to dissect the consequences of the selective abrogation of endogenous MHCII expression by LECs and/or FRCs on self-reactive CD4+ T cell responses, and the subsequent impact on autoimmunity development. Aim 2 will identify the molecular pathways by which LECs and FRCs present self-Ags through MHCII molecules. In particular, we will determine whether those cells, similarly to mTECs, can target PTAs to the autophagic pathway and deliver them to MHCII compartments. Alternatively, stromal cell-unsheathed conduit networks transport small Ags, which raise the hypothesis that LECs and FRCs acquire exogenous self-Ags and present them via MHCII molecules to CD4+ T cells. Notably, in the context of tumor development, LECs substantially expand and lymphatic drainage is consequently increased in both the tumor itself and tumor-draining LNs. Furthermore, LN-like structures develop intratumorally and exhibit most of FRC features. Therefore, LEC and FRC ability to capture Ags will be potentially enhanced in a tumoral context. Aim 3 will therefore determine the role of Ag-presentation by LECs and FRCs in tumor immunity. We will dissect the molecular and cellular features of tumor-associated LECs and FRCs in their ability to capture and present tumor Ags to CD4+ T cells, and how the selective abrogation of those functions will impact anti-tumor T cell immunity and tumor growth. These aims will be addressed using various gene-targeted mouse strains, amongst them mice in which LECs or FRCs are deficient or enhanced for specific functions, in combination with fluorescent reporter mice, in vivo mouse model of diseases and functional T cell analysis.Overall, our project will generate fundamental new insights into the contribution of LNSCs, in particular LECs and FRCs, to peripheral T cell responses as unconventional Ag presenting cells (APCs). Emerging perception of our understanding from recent studies suggests that LNSCs would function as tolerogenic APCs. A confirmation of this concept would significantly change and extend the current perspective on how to promote or in contrast inhibit T cell tolerance in the treatment of autoimmune diseases and cancer development, respectively.
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