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
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.
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.
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.
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.
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.
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.
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.
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.
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
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)
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
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
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.