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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 128394
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 01.09.2010 - 31.08.2014
Approved amount 1'586'424.00
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All Disciplines (2)

Discipline
Immunology, Immunopathology
Cellular Biology, Cytology

Keywords (12)

T lymphocyte; dendritic cell; self-tolerance; mouse models; autoimmune diseases; intravital imaging; experimental autoimmune encephalomyelitis; lymphoid organs; brain; T cell; tolerance; autoimmune disease

Lay Summary (English)

Lead
Lay summary
The main mediators of adaptive 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. 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. 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 in the induction of T cell tolerance, a key process in avoiding autoimmunity. 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. This work, therefore, 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) to dissect the mechanisms that allow for pDC-induced T cell tolerance and, thus, protect the host from autoimmunity. The long-term aim is to define new molecular and cellular pDC targets for manipulating the immune system in the treatment of autoimmune diseases. A further long-term objective of the work proposed here is to expand these studies into oncology and to understand why some tumors are not efficiently eradicated by the immune system. Indeed, by manipulating the pDC responses in tumor models, this project may provide insights into mechanisms to ameliorate current cancer immunotherapy. This work will give a better understanding on the specific subtypes of DC competent to induce T cell tolerance. An immediate consequence is that vaccination protocols using DC for cancer treatments should be defined carefully by taking the tolerogenic potential of pDC cells into account (for instance by depleting this DC subset prior patient vaccination).
Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
Lymph node stromal cells acquire peptide-MHCII complexes from dendritic cells and induce antigen-specific CD4⁺ T cell tolerance
Dubrot Juan (2014), Lymph node stromal cells acquire peptide-MHCII complexes from dendritic cells and induce antigen-specific CD4⁺ T cell tolerance, in Journal of Experimental Medicine, 211(6), 1153-1166.
Steady-state antigen scavenging, cross-presentation, and CD8+ T cell priming: a new role for lymphatic endothelial cells.
Hirosue Sashiko (2014), Steady-state antigen scavenging, cross-presentation, and CD8+ T cell priming: a new role for lymphatic endothelial cells., in Journal of Immunology, 192(11), 5002-5011.
Plasmacytoid dendritic cells control T-cell response to chronic viral infection.
Cervantes-Barragan Luisa, Lewis Kanako L, Firner Sonja, Thiel Volker, Hugues Stephanie, Reith Walter, Ludewig Burkhard, Reizis Boris (2012), Plasmacytoid dendritic cells control T-cell response to chronic viral infection., in Proceedings of the National Academy of Sciences of the United States of America, 109(8), 3012-7.
VEGF-C promotes immune tolerance in B16 melanomas and cross-presentation of tumor antigen by lymph node lymphatics.
Lund Amanda W, Duraes Fernanda V, Hirosue Sachiko, Raghavan Vidya R, Nembrini Chiara, Thomas Susan N, Issa Amine, Hugues Stéphanie, Swartz Melody A (2012), VEGF-C promotes immune tolerance in B16 melanomas and cross-presentation of tumor antigen by lymph node lymphatics., in Cell reports, 1(3), 191-9.
Dynamics of dendritic cell-T cell interactions: a role in T cell outcome.
Hugues Stéphanie (2010), Dynamics of dendritic cell-T cell interactions: a role in T cell outcome., in Seminars in immunopathology, 32(3), 227-38.
MHC class II-restricted antigen presentation by plasmacytoid dendritic cells inhibits T cell-mediated autoimmunity.
Irla Magali, Küpfer Natalia, Suter Tobias, Lissilaa Rami, Benkhoucha Mahdia, Skupsky Jonathan, Lalive Patrice H, Fontana Adriano, Reith Walter, Hugues Stéphanie (2010), MHC class II-restricted antigen presentation by plasmacytoid dendritic cells inhibits T cell-mediated autoimmunity., in The Journal of experimental medicine, 207(9), 1891-905.
Ag-presenting CpG-activated pDCs prime Th17 cells that induce tumor regression
Guery Leslie, Ag-presenting CpG-activated pDCs prime Th17 cells that induce tumor regression, in Cancer Research.
MHC Class II-Restricted Antigen Presentation by Plasmacytoid Dendritic Cells Drives Pro-Atherogenic T Cell Immunity
Sage A, MHC Class II-Restricted Antigen Presentation by Plasmacytoid Dendritic Cells Drives Pro-Atherogenic T Cell Immunity, in Circulation.
Role of major histocompatibility complex class II expression by non-hematopoietic cells in autoimmune and inflammatory disorders: facts and fiction
Duraes Fernanda, Role of major histocompatibility complex class II expression by non-hematopoietic cells in autoimmune and inflammatory disorders: facts and fiction, in Tissue Antigens.
Tolerogenic and activatory plasmacytoid dendritic cells in autoimmunity
Guéry Leslie, Tolerogenic and activatory plasmacytoid dendritic cells in autoimmunity, in Front Immunol.

Collaboration

Group / person Country
Types of collaboration
Ziad Mallat, University of Cambridge Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Ron Germain NIH United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
EPFL- Prof. Melody Swartz Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication

Scientific events



Self-organised

Title Date Place
Club Francophone des cellules dendritiques-membre organisateur 08.12.2011 Paris, France

Awards

Title Year
Leenaards Foundation (Laureates: Prof. Hugues et Prof. Swartz) 2011

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

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. This work, therefore, 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) to dissect the mechanisms that allow for pDC-induced T cell tolerance and, thus, protect the host from autoimmunity. 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. In particular, the pDC involvement in the generation and maintenance of a tolerogenic state in diseases will be investigated. pDC tolerogenic properties will be carefully analyzed in term of DC phenotype, in vivo DC-T cell interaction dynamics, and T cell outcome and compared to cDC. The contribution/cooperation of both DC subsets in the induction/maintenance of tolerance towards self-antigens will be investigated in vivo using different mouse models for autoimmune diseases. 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). The main objective of this study, therefore, is to define new molecular and cellular biomarkers of pDC activity and, thus, identify potential therapeutic targets for manipulating the immune system in the treatment of debilitating autoimmune diseases. A further long-term 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. Indeed, by manipulating the pDC responses in tumor models, this project may provide insights into mechanisms to ameliorate current cancer immunotherapy. This work will give a better understanding on the specific subtypes of dendritic cells competent to induce T cell tolerance. An immediate consequence is that vaccination protocols using dendritic cells for cancer treatments should be defined carefully by taking the tolerogenic potential of pDC in account.
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