Project

Back to overview

The study of how plasmacytoid dendritic cells can be manipulated to control inflammatory and autoimmune diseases

English title The study of how plasmacytoid dendritic cells can be manipulated to control inflammatory and autoimmune diseases
Applicant Hugues Stéphanie
Number 152951
Funding scheme SNSF Professorships
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 01.09.2014 - 31.08.2016
Approved amount 749'177.00
Show all

All Disciplines (2)

Discipline
Immunology, Immunopathology
Cellular Biology, Cytology

Keywords (9)

dendritic cell; mouse models; cancers; self-tolerance; intravital imaging; lymph node stromal cells; autoimmune diseases; lymphoid organs; T lymphocyte

Lay Summary (French)

Lead
Notre système immunitaire a mis en place des mécanismes permettant d’éliminer de façon la plus efficace possible les pathogènes (virus, bactéries, …) tout en restant « neutre » vis à vis de nos propres tissus. Cette dernière fonction est appelée tolérance immune vis à vis du soi. Lorsque les lymphoytes T, des acteurs très importants de notre système immunitaire, sont sélectionnés dans le thymus, ceux qui présentent une réactivité pour les tissus du soi dont normalement éliminés. Cependant, cette sélection thymique est imparfaite, et des lymphocytes T reconnaissant le soi circulent dans nos organes lymphoides secondaires, pouvant potentiellement entrainer le développement de maladies autoimmunes. Par conséquent, des mécanismes additionnels, dit de tolérance en périphérie, ont été mis en place afin de maitenir la tolérance vis à vis du soi. Ce projet dissèque la contribution des différentes cellules résidant dans nos organes lymphoides secondaires sont impliquées dans ce processus.
Lay summary

Depuis les années 1970, les cellules dendritiques (CD) ont été décrites comme des cellules spécialisées dans la présentation des antigènes et l’activation des lymphocytes T spécifiques des ces antigènes. Les CD sont donc des cellules présentatrices d’antigènes professionnelles qui sont considérées comme des sentiennelles de notre système immunitaire. Elles sont été plus récemment décrites, il y a une quinzaine d’années, comme importante dans la présentation des antigènes du soi, l’inactivation des lymphocytes T autoréactifs, et donc le maintien de la tolérance vis à vis du soi. Ce projet étudie la contribution d’un sous-type particuler de CD, les CD plasmacytoides, dans le maintien de la tolérance périphérique. En utilisant des modèles murins, nous étudions notamment les mécanismes expliquant pourquoi dans certaines situations inflammatoires comme le developpement de maladies autoimmunes, alors que les CD dites conventionnelles perdent la capacité de maintenir une tolérance périphérique, les CD plamacytoides maintiennent cette fonction. Plus récemment, d’autres cellules résidant dans les organes lymphoides secondaires, les cellules stromales, qui étaient à l’origine des piliers structuraux et architecturaux des organes lymphoides secondaires, ont également été décrites pour être impliquées dans la tolérance périphérique. Nous étudions leur rôle dans l’inactivation des lymphocytes T autoréactifs, qui semble lié à leur capacité d’exprimer et de présenter aux lymphocytes T des antigènes normalement spécifiques de tissus particuliers.

Le projet relève de la recherche fondamentale, et utilise des souris génétiquement modifiées permettent d’abolir spécifiquement une fonction particulière d’un type particulier de cellules, et d’analyser les conséquences sur la réponse des lymphocytes T autoréactifs, notamment au cours du développement de modèle murins de maladies autoimmunes.

 

Direct link to Lay Summary Last update: 03.07.2014

Responsible applicant and co-applicants

Employees

Publications

Publication
Intratumoral CpG-B Promotes Antitumoral Neutrophil, cDC, and T-cell Cooperation without Reprograming Tolerogenic pDC
HumbertMarion, GueryLeslie, BrighouseDale, LemeilleSylvain, HuguesStephanie (2018), Intratumoral CpG-B Promotes Antitumoral Neutrophil, cDC, and T-cell Cooperation without Reprograming Tolerogenic pDC, in Cancer Research, 78(12), 3280-3292.
STIM1 promotes migration, phagosomal maturation and antigen cross-presentation in dendritic cells
Nunes-Hasler Paula, Maschalidi Sophia, Lippens Carla, Castelbou Cyril, Bouvet Samuel, Guido Daniele, Bermont Flavien, Bassoy Esen Y., Page Nicolas, Merkler Doron, Hugues Stéphanie, Martinvalet Denis, Manoury Bénédicte, Demaurex Nicolas (2017), STIM1 promotes migration, phagosomal maturation and antigen cross-presentation in dendritic cells, in Nature Communications, 8(1), 1852-1852.
Pannexin1 links lymphatic function to lipid metabolism and atherosclerosis
Molica Filippo, Meens Merlijn J., Dubrot Juan, Ehrlich Avigail, Roth Christel L., Morel Sandrine, Pelli Graziano, Vinet Laurent, Braunersreuther Vincent, Ratib Osman, Chanson Marc, Hugues Stephanie, Scemes Eliana, Kwak Brenda R. (2017), Pannexin1 links lymphatic function to lipid metabolism and atherosclerosis, in Scientific Reports, 7(1), 13706-13706.
Cx47 fine-tunes the handling of serum lipids but is dispensable for lymphatic vascular function
Meens Merlijn J., Kutkut Issa, Rochemont Viviane, Dubrot Juan, Kaladji Fouad R., Sabine Amélie, Lyons Oliver, Hendrikx Stefanie, Bernier-Latmani Jeremiah, Kiefer Friedemann, Smith Alberto, Hugues Stéphanie, Petrova Tatiana V., Kwak Brenda R. (2017), Cx47 fine-tunes the handling of serum lipids but is dispensable for lymphatic vascular function, in PLOS ONE, 12(7), e0181476-e0181476.
The Heterogeneity of Ly6Chi Monocytes Controls Their Differentiation into iNOS+ Macrophages or Monocyte-Derived Dendritic Cells
Menezes Shinelle, Melandri Daisy, Anselmi Giorgio, Perchet Thibaut, Loschko Jakob, Dubrot Juan, Patel Rajen, Gautier Emmanuel L., Hugues Stéphanie, Longhi M. Paula, Henry Jake Y., Quezada Sergio A., Lauvau Grégoire, Lennon-Duménil Ana-Maria, Gutiérrez-Martínez Enrique, Bessis Alain, Gomez-Perdiguero Elisa, Jacome-Galarza Christian E., Garner Hannah, Geissmann Frederic, Golub Rachel, Nussenzweig Michel C., Guermonprez Pierre (2016), The Heterogeneity of Ly6Chi Monocytes Controls Their Differentiation into iNOS+ Macrophages or Monocyte-Derived Dendritic Cells, in Immunity, 45(6), 1205-1218.
Btn2a2, a T cell immunomodulatory molecule coregulated with MHC class II genes
Sarter Kerstin, Sarter Kerstin (2016), Btn2a2, a T cell immunomodulatory molecule coregulated with MHC class II genes, in J Exp Med, 177.
Immune tolerance. Group 3 innate lymphoid cells mediate intestinal selection of commensal bacteria-specific CD4⁺ T cells.
Hepworth MR Fung TC Masur SH Kelsen JR McConnell FM Dubrot J Withers DR Hugues S Farrar MA, Hepworth MR Fung TC Masur SH Kelsen JR McConnell FM Dubrot J Withers DR Hugues S Farrar MA (2015), Immune tolerance. Group 3 innate lymphoid cells mediate intestinal selection of commensal bacteria-specific CD4⁺ T cells., in Science, 1031.
Macroautophagy in Endogenous Processing of Self- and Pathogen-Derived Antigens for MHC Class II Presentation.
Duraes FV Niven J Dubrot J Hugues S Gannagé M., Duraes FV Niven J Dubrot J Hugues S Gannagé M. (2015), Macroautophagy in Endogenous Processing of Self- and Pathogen-Derived Antigens for MHC Class II Presentation., in Frontiers in Immunology, 459.
Oxysterols regulate encephalitogenic CD4(+) T cell trafficking during central nervous system autoimmunity.
Chalmin F Rochemont V Lippens C Clottu A Sailer AW Merkler D Hugues S Pot C, Chalmin F Rochemont V Lippens C Clottu A Sailer AW Merkler D Hugues S Pot C (2015), Oxysterols regulate encephalitogenic CD4(+) T cell trafficking during central nervous system autoimmunity., in Journal of Autoimmunity, 45.
IDO-orchestrated crosstalk between pDCs and Tregs inhibits autoimmunity.
Lippens Carla, Lippens Carla, IDO-orchestrated crosstalk between pDCs and Tregs inhibits autoimmunity., in Journal if autoimmunity.
New role for antigen-presenting activated pDCs in promoting Th17 cells and impacting antitumor immunity.
Guéry L. Hugues S., Guéry L. Hugues S., New role for antigen-presenting activated pDCs in promoting Th17 cells and impacting antitumor immunity., in Oncoimmunology.
pDC therapy induces recovery from EAE by recruiting endogenous pDC to sites of CNS inflammation.
Duraes FV Lippens C Steinbach K Dubrot J Brighouse D Bendriss-Vermare N Issazadeh-Navikas S M, Duraes FV Lippens C Steinbach K Dubrot J Brighouse D Bendriss-Vermare N Issazadeh-Navikas S M, pDC therapy induces recovery from EAE by recruiting endogenous pDC to sites of CNS inflammation., in Journal of Autoimmunity.

Collaboration

Group / person Country
Types of collaboration
T. Blankenstein Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
R. Germain NIH United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
D. Chudakov Russia (Europe)
- in-depth/constructive exchanges on approaches, methods or results
T. Petrova Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Caroline Pot, CHUV Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
W. Reith, Centre Médical Universitaire, Genève Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
M. Gannagé Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
G. Kaya Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
M. Swartz, EPFL, Lausanne Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
T. McKee Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
Seminars in Immunology & Infection Biology Individual talk Lymph nodes stromal cells in peripheral T cell tolerance 12.12.2017 Zurich, Switzerland Hugues Stéphanie;
FORUM Graduate Schools Infection & Immunity Talk given at a conference Lymph node stromal cells in peripheral T cell tolerance 12.05.2017 Geneva, Switzerland Hugues Stéphanie;
CTPT Research Center Individual talk Lymph node stromal cells in peripheral T cell tolerance 10.11.2016 Toulouse, France Hugues Stéphanie;
Annual Congress of Cytometry Talk given at a conference Unconventional antigen presenting cell in T cell tolerance 18.11.2015 Antibes, France Hugues Stéphanie;
Bern Immunology Club Individual talk Unconventional antigen presenting cells in T cell tolerance 29.04.2015 bern, Switzerland Hugues Stéphanie;


Associated projects

Number Title Start Funding scheme
128394 The study of how plasmacytoid dendritic cells can be manipulated to control inflammatory and autoimmune diseases 01.09.2010 SNSF Professorships
166541 MHCII mediated Antigen-presentation by Lymph Node Stromal Cells in Autoimmunity and Cancer 01.09.2016 Project funding

Abstract

The main mediators of immunity are B and T lymphocytes, but their function is under the control of dendritic cells (DC). DC in the periphery capture and process antigens (Ag), express lymphocyte co-stimulatory molecules, migrate to lymphoid organs and secrete cytokines to initiate immune responses. They not only activate lymphocytes, they also tolerize T cells to Ag that are innate to the body (self-antigens), thereby minimizing autoimmune reactions. Once a neglected cell type, DC can now be readily obtained in sufficient quantities to allow molecular and cell biological analysis. It has become increasingly evident that these cells are a powerful tool for manipulating the immune system. DC are generally classified as either conventional (cDC) or plasmacytoid (pDC). It is well established that cDC function as sentinels of the adaptive immune system. They reside in peripheral tissues, sample their surroundings and migrate to secondary lymphoid tissues to present foreign or host Ag to T cells. Under neutral or non-inflammatory conditions, cDC are, paradoxically, able to induce initially a transient activation of host Ag-specific T cells followed by a rapid shutdown of these T cells resulting in tolerance. Inflammatory immune responses, however, cause DC maturation and results in rapid and effective T cell responses. In contrast to cDC, pDC were initially believed to be involved primarily in innate, or first-line, immune responses via the secretion of type I interferons following viral or bacterial infections. However, very recent findings demonstrate that like cDC, pDC are also implicated in adaptive immune responses. Exciting new developments in pDC biology further implicates these cells directly in the induction of T cell tolerance, a key process in avoiding autoimmunity. Thus, nature has developed a unique system of whereby the hosts immune response, via pDC, present Ag to potentially autoimmune-inducing T cells in order for them to be rendered anergic or non-responsive. These processes are at the infancy of being elucidated and further work will potentially open new avenues to the therapeutic treatment, via pDC manipulation, in the aim of controlling debilitating autoimmune diseases. This proposal will allow the intricate in vivo analysis of the impact on immune responses following the selective loss of Ag presentation function by pDC. In particular, the pDC involvement in the generation and maintenance of a tolerogenic state in diseases will be investigated. The mechanisms that allow for pDC-induced T cell tolerance and, thus, protect the host from autoimmunity, will be dissected.These models of tolerance involving cDC and/or pDC limit the presentation of particular Ags to the lymph nodes draining the tissues in which the Ag is expressed. An alternative mechanism, involving non-hematopoietic lymph node stromal cells (LNSC), has recently emerged. Indeed, these cells were recently shown to not only function as passive conduits in lymph nodes, but also to contribute to peripheral T cell responses. First, they produce soluble mediators that indirectly alter T cell and DC functions and consequently impact T cell responses. Second, they endogenously express self-Ags - a feature thought to be restricted to medullary thymic epithelial cells- and present these self-Ags to CD8+ T cells to induce their deletion, thus contributing to CD8+ T cell tolerance. Whether LNSC can similarly impact CD4+ T cell responses is totally unknown. One exciting hypothesis we are testing that LNSC present Ag to CD4+ T cells and directly impact peripheral CD4+ T cell responses.This work entails the use of cutting edge techniques (including two-photon intravital imaging on live animals) and animal models of disease (e.g. multiple sclerosis, autoimmune diabetes, tumors) to dissect the mechanisms that allow for hematopoietic and non-hematopoietic Ag presenting cells-induced T cell tolerance and, thus, protect the host from autoimmunity and cancers. The main objective of this study is to define new molecular and cellular biomarkers and, thus, identify potential therapeutic targets for manipulating the immune system in the treatment of debilitating autoimmune diseases. A further objective of the proposal is to expand these studies into oncology and to understand why some tumors are not efficiently eradicated by the immune system.
-