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Regulation of MHC class II expression and antigen presenting cell function

English title Regulation of MHC class II expression and antigen presenting cell function
Applicant Reith Walter
Number 127255
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 01.01.2010 - 31.12.2012
Approved amount 840'000.00
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All Disciplines (2)

Discipline
Immunology, Immunopathology
Molecular Biology

Keywords (13)

molecular immunology; Major Histocompatibility Complex class II; antigen presentation; antigen presenting cells; regulation of gene expression; transcription; knockout and transgenic mouse models; medullary thymic epihelial cells; thymic development and function; immunology; MHC class II; CD4+ T lymphocytes; thymus development and function

Lay Summary (English)

Lead
Lay summary
Major Histocompatibility Complex class II (MHCII) molecules play central roles in the immune system. They are expressed at the surface of specialized cells - referred to as antigen presenting cells (APCs) - and serve as display cases that present antigens to helper (CD4+) T lymphocytes. The recognition of MHCII-antigen complexes by CD4+ T cells is essential for the development of these cells in the thymus, and for their ability to initiate and regulate antigen specific immune responses directed against infectious agents and tumors. The aberrant recognition of self-antigens presented by MHCII molecules also underlies the development of life-threatening autoimmune diseases. The immunological processes involving MHCII molecules depend on an appropriately regulated cell-type specific pattern of MHCII expression. Deficient or deregulated MHCII expression has profound pathological consequences. We are therefore pursuing a longstanding interest in deciphering the mechanisms that regulate MHCII expression. Our ongoing studies are concentrating on the following four aspects. First, we are characterizing the molecular mechanisms that activate the expression of MHCII genes in various types of APCs. We are in particular exploring the possibility that the activation of individual MHCII genes may be superimposed by global regulatory mechanisms affecting the entire MHCII gene family. Second, we are studying how silencing of MHCII expression is achieved in certain key types of APC, and whether this repression mechanism is of widespread importance for the function of these cells. Third, we are in the process of defining the functions of newly identified genes that are co-regulated with MHCII genes. We are in particular concentrating on a novel gene of unknown function that is tightly controlled by the same regulatory machinery that is dedicated for MHCII expression, and which may play a key accessory role in antigen presentation and the development and/or activation CD4+ T cells. Finally, we are studying the function of MHCII expression in development of the thymus. We are notably examining how MHCII expression contributes to the development and function of specialized epithelial cells present in the medullar region of the thymus. These cells are of particular interest because they play key roles in the establishment of immunological self-tolerance. Taken together, the results obtained during the course of our work will further our understanding of the molecular and cellular mechanisms that regulate MHCII-mediated antigen presentation in healthy individuals and shed new light on the deregulation of these mechanisms during the course of disease.
Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
Three-dimensional visualization of the mouse thymus organization in health and immunodeficiency.
Irla Magali, Guenot Jeanne, Sealy Gregg, Reith Walter, Imhof Beat A, Sergé Arnauld (2013), Three-dimensional visualization of the mouse thymus organization in health and immunodeficiency., in Journal of immunology (Baltimore, Md. : 1950), 190(2), 586-96.
Antigen recognition by autoreactive CD4⁺ thymocytes drives homeostasis of the thymic medulla.
Irla Magali, Guerri Lucia, Guenot Jeanne, Sergé Arnauld, Lantz Olivier, Liston Adrian, Imhof Beat A, Palmer Ed, Reith Walter (2012), Antigen recognition by autoreactive CD4⁺ thymocytes drives homeostasis of the thymic medulla., in PloS one, 7(12), 52591-52591.
Novel murine dendritic cell lines: a powerful auxiliary tool for dendritic cell research.
Fuertes Marraco Silvia A, Grosjean Frédéric, Duval Anaïs, Rosa Muriel, Lavanchy Christine, Ashok Devika, Haller Sergio, Otten Luc A, Steiner Quynh-Giao, Descombes Patrick, Luber Christian A, Meissner Felix, Mann Matthias, Szeles Lajos, Reith Walter, Acha-Orbea Hans (2012), Novel murine dendritic cell lines: a powerful auxiliary tool for dendritic cell research., in Frontiers in immunology, 3, 331-331.
Two rotating cilia in the node cavity are sufficient to break left-right symmetry in the mouse embryo.
Shinohara Kyosuke, Kawasumi Aiko, Takamatsu Atsuko, Yoshiba Satoko, Botilde Yanick, Motoyama Noboru, Reith Walter, Durand Bénédicte, Shiratori Hidetaka, Hamada Hiroshi (2012), Two rotating cilia in the node cavity are sufficient to break left-right symmetry in the mouse embryo., in Nature communications, 3, 622-622.
Cx36 is a target of Beta2/NeuroD1, which associates with prenatal differentiation of insulin-producing β cells.
Nlend Rachel Nlend, Aït-Lounis Aouatef, Allagnat Florent, Cigliola Valentina, Charollais Anne, Reith Walter, Haefliger Jacques-Antoine, Meda Paolo (2012), Cx36 is a target of Beta2/NeuroD1, which associates with prenatal differentiation of insulin-producing β cells., in The Journal of membrane biology, 245(5-6), 263-73.
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.
Autoimmunity and inflammation are independent of class II transactivator type PIV-dependent class II major histocompatibility complex expression in peripheral tissues during collagen-induced arthritis.
Waldburger Jean-Marc, Palmer Gaby, Seemayer Christian, Lamacchia Celine, Finckh Axel, Christofilopoulos Panayiotis, Baeten Dominique, Reith Walter, Gabay Cem (2011), Autoimmunity and inflammation are independent of class II transactivator type PIV-dependent class II major histocompatibility complex expression in peripheral tissues during collagen-induced arthritis., in Arthritis and rheumatism, 63(11), 3354-63.
Silencing of c-Fos expression by microRNA-155 is critical for dendritic cell maturation and function.
Dunand-Sauthier Isabelle, Santiago-Raber Marie-Laure, Capponi Leonardo, Vejnar Charles E, Schaad Olivier, Irla Magali, Seguín-Estévez Queralt, Descombes Patrick, Zdobnov Evgeny M, Acha-Orbea Hans, Reith Walter (2011), Silencing of c-Fos expression by microRNA-155 is critical for dendritic cell maturation and function., in Blood, 117(17), 4490-500.
Long term amelioration of established collagen-induced arthritis achieved with short term therapy combining anti-CD3 and anti-TNF treatments
Dépis F., Hatterer E., Lamacchia C., Waldburger J.-M., Gabay C., Reith W., Kosco-Vilbois M., Dean Y., Long term amelioration of established collagen-induced arthritis achieved with short term therapy combining anti-CD3 and anti-TNF treatments, in Arthritis and Rheumatism.
NLRC5 Deficiency Selectively Impairs MHC Class I- Dependent Lymphocyte Killing by Cytotoxic T Cells.
Staehli Francesco, Ludigs Kristina, Heinz Leonhard X, Seguín-Estévez Queralt, Ferrero Isabel, Braun Marion, Schroder Kate, Rebsamen Manuele, Tardivel Aubry, Mattmann Chantal, Macdonald H Robson, Romero Pedro, Reith Walter, Guarda Greta, Tschopp Jürg, NLRC5 Deficiency Selectively Impairs MHC Class I- Dependent Lymphocyte Killing by Cytotoxic T Cells., in Journal of immunology (Baltimore, Md. : 1950).
The CEACAM1 tumor suppressor is an ATM and p53 regulated gene required for the induction of cellular senescence by DNA damage
Sappino A.-P., Buser R., Sequin-Estevez Q., Fernet M., Lesne L., Gumy-Pause F., Reith W., Favaudon V., Mandriota S.J., The CEACAM1 tumor suppressor is an ATM and p53 regulated gene required for the induction of cellular senescence by DNA damage, in Oncongenesis.
The Ciliogenic transcription factor Rfx3 regulates early midline distribution of guidepost neurons required for corpus callosum development
Benadiba C., Magnani D., Niquille M., Morlé L., Valloton D., Nawabi H., Ait-Lounis A., Otsmane B., Reith W., Theil T., Hornung J.-P., Lebrand C., Durand B., The Ciliogenic transcription factor Rfx3 regulates early midline distribution of guidepost neurons required for corpus callosum development, in PLoS Genetics.

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
CFCD Annual Meeting "Diversity and Plasticity of DCs" 13.12.2012 Paris, France
10th Joint Annual Meeting of the International Cytokine Society (ICS) and International Society for Interferon and Cytokine Research (ISICR) 11.09.2012 Geneva, Switzerland
European Congress of Immunology 05.09.2012 Glasgow, Scotland
European Macrophage and Dendritic Cell Society (EMDS) meeting 2012 01.09.2012 Debrecen, Hungary
Lecture 30.09.2011 Lausanne, Imunology Summer School
Lecture 30.04.2011 Institute for Research in Biomedicine, Belinzona


Awards

Title Year
Biogen-Dompé research award from the Swiss MS Society to Magali Irla and Stéphanie Hugues 2011
Promotion of Walter Reith to Chairmann of the Department of Pathology and Immunology, Medical School 2011
SNSF Ambizione fellowship to Magali Irla 2011
SNSF professorship to Stéphanie Hugues 2011

Associated projects

Number Title Start Funding scheme
144085 Regulation of antigen presentation and antigen presenting cell function 01.01.2013 Project funding
121418 Ultra High Throughput sequencing platform for functional genome analysis 01.08.2008 R'EQUIP
105895 Regulation and deregulation of MHC class II genes 01.01.2005 Project funding

Abstract

The recognition of peptides by T cells is critical for their development and function. CD4+ T cells recognize peptides bound to Major Histocompatibility Complex class II (MHCII) molecules expressed at the surface of cell types specialized for antigen presentation, including mainly cortical and medullary thymic epithelial cells (TEC) and professional antigen presenting cells (APC), namely various dendritic cell (DC) subtypes, B cells and macrophages. MHCII-mediated peptide presentation by these cells orchestrates several pivotal processes, including T cell development in the thymus, the establishment of thymic self-tolerance, the maintenance of tolerance in the periphery, and the initiation, regulation and propagation of adaptive immune responses directed against pathogens and tumors. These processes depend on a precise cell-type specific and quantitatively controlled pattern of MHCII expression, and deficient or deregulated MHCII expression consequently has profound pathological consequences. We have a long-standing interest in deciphering the molecular mechanisms that regulate MHCII expression. The work proposed here will be divided into four projects (A-D) that have developed directly from our previous research in the field of MHCII gene regulation. These projects address novel questions concerning the mechanisms that regulate MHCII expression, the specificity of these mechanisms, and their contributions to the functions of APC and TEC. Subproject A will study whether the activation of individual MHCII promoters is superimposed by global regulatory mechanisms that are mediated by long-distance chromatin interactions establishing a three-dimensional structure at the MHCII locus. This work should open up a new dimension in the regulation of MHCII expression and shed light on structural and/or functional constraints that may have shaped the conserved domain architecture of the MHCII locus during evolution. Subproject B will study the molecular mechanisms that induce epigenetic silencing of the gene encoding CIITA (the master regulator of MHCII expression) during the maturation of DC, and determine how these mechanisms contribute to rapid and widespread remodeling of the transcription program during DC maturation, a process that is critical for the initiation of effective adaptive immune responses. Subproject C will study the function of BTN2a2, a gene of unknown function that is expressed mainly in B cells, endothelial cells and TEC, and is controlled by the same regulatory machinery that is dedicated for MHCII expression. As BTN2a2 is a relative of the B7 family of immunomodulatory molecules, our results are likely to further our understanding of the mechanisms that modulate thymic function and/or adaptive immune responses. The aim of subproject D is to unravel the role of MHCII expression in the development and function of medullary TEC, a unique cell type that plays pivotal roles in the establishment and maintenance of self-tolerance by inducing the deletion of autoreactive thymocytes and by contributing to the development of natural regulatory T cells. These projects will employ a combination of classical molecular, biochemical and cellular methods, more sophisticated state-of-the-art techniques (large scale ChIP-chip and ChIP-seq screens, engineering of large DNA constructs by BAC recombineering, analysis of long-distance chromatin interactions by 3C and 4C strategies, high throughput sequencing), and in vivo approaches using various transgenic and knockout mouse models, including the generation and analysis of new strains of conventional and conditional knockout mice. Taken together, the combined work will extend our knowledge on the mechanisms controlling the expression of MHCII and coregulated genes, and broaden our understanding of the importance of these processes by studying their more widespread relevance to the development and/or function of TEC and key APC, particularly medullary TEC, B cells and DC.
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