Project

Back to overview

Expression, function and mechanism of action of BTN2A2, a new costimulatory molecule coregulated with MHC class II expression

English title Expression, function and mechanism of action of BTN2A2, a new costimulatory molecule coregulated with MHC class II expression
Applicant Reith Walter
Number 166371
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 01.04.2016 - 31.03.2019
Approved amount 1'045'223.00
Show all

All Disciplines (5)

Discipline
Immunology, Immunopathology
Cellular Biology, Cytology
Biochemistry
Physiology : other topics
Genetics

Keywords (10)

Major Histocompatibility Complex class II; molecular immunology; T cell immunology; negative costimulatory molecules; adaptive immunity; butyrophylin proteins; BTN2A2; antigen presenting cells; knockout and transgenic mouse models; checkpoint regulators

Lay Summary (French)

Lead
Le système immunitaires permet à l'organisme de se défendre contre des infections et de se prémunir contre le développement de tumeurs. Si le système immunitaire est perturbée, elle peut aussi entrainer des pathologies, comme des maladies auto-immunes. Nous avons récemment identifié une nouvelle protéine, appelée BTN2A2, qui agit comme un frein sur les réponses immunes chez la souris. Elle atténue aussi bien des réponses immunes normales, comme celles dirigés contre des antigène étrangers ou contre des tumeurs, que des réponses immunes pathologiques, comme celles impliquées dans les maladies auto-immunes. Le but de notre projet est d'élucider les mécanismes cellulaires et moléculaires responsables de ces fonctions immuno-régulatrices de BTN2A2.
Lay summary

Les objectifs principaux de nos recherches portant sur la molécule BTN2A2 sont (a) d'étudier l'expression de BTN2A2 in vivo, (b) d'évaluer l'importance de BTN2A2 dans la régulation de différentes réponses immune normales et pathologiques, (c) d’élucider les mécanismes cellulaires et moléculaires par le biais desquels BTN2A2 inhibe les réponses immunes, (d) de déterminer si ces mécanismes sont conservés chez l’homme, et (d) d'investiguer la possibilité que cette nouvelle voie immuno-régulatrice pourrait constituer une nouvelle cible thérapeutique pour des maladies impliquant la réponses immunitaire.

Ces études apporteront de nouvelles connaissances fondamentales sur le fonctionnement du système immunitaire. Elles permettront notamment de mieux comprendre une nouvelle voie de régulation des réponses immunes. Nos recherches permettront également de déterminer si cette nouvelle voie de régulation pourrait être exploité dans un but thérapeutique chez l'homme, notamment pour traiter des maladies auto-immunes ou pour renforcer des réponses immunes dirigées contre des cancers. 

 

Direct link to Lay Summary Last update: 30.03.2016

Responsible applicant and co-applicants

Employees

Publications

Publication
Butyrophilin (BTN) family interactions
Rhodes DA, ReithWalter (2017), Butyrophilin (BTN) family interactions, 60, Reactome Pathway Knowledgebase, USA 60.
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.
Spatiotemporal expression of endogenous TLR4 ligands leads to inflammation and bone erosion in mouse collagen-induced arthritis
Kiyeko Gaëlle Wambiekele, Hatterer Eric, Herren Suzanne, Di Ceglie Irene, van Lent Peter L., Reith Walter, Kosco-Vilbois Marie, Ferlin Walter, Shang Limin (2016), Spatiotemporal expression of endogenous TLR4 ligands leads to inflammation and bone erosion in mouse collagen-induced arthritis, in European Journal of Immunology, 46(11), 2629-2638.
Mammalian Innate Immune Response to a Leishmania -Resident RNA Virus Increases Macrophage Survival to Promote Parasite Persistence
Eren Remzi Onur, Reverte Marta, Rossi Matteo, Hartley Mary-Anne, Castiglioni Patrik, Prevel Florence, Martin Ricardo, Desponds Chantal, Lye Lon-Fye, Drexler Stefan K., Reith Walter, Beverley Stephen M., Ronet Catherine, Fasel Nicolas (2016), Mammalian Innate Immune Response to a Leishmania -Resident RNA Virus Increases Macrophage Survival to Promote Parasite Persistence, in Cell Host & Microbe, 20(3), 318-328.
Regulation of Immunity by Butyrophilins
Rhodes David A., Reith Walter, Trowsdale John (2016), Regulation of Immunity by Butyrophilins, in Annual Review of Immunology, 34(1), 151-172.
Major Histocompatibility Complex Class II Deficiency
PicardCapucine, ReithWalter (2016), Major Histocompatibility Complex Class II Deficiency, in Ratcliffe Michael (ed.), Academic Press, United States of America, 378-390.
T Cell Priming by Activated Nlrc5-Deficient Dendritic Cells Is Unaffected despite Partially Reduced MHC Class I Levels.
Rota Giorgia, Ludigs Kristina, Siegert Stefanie, Tardivel Aubry, Morgado Leonor, Reith Walter, De Gassart Aude, Guarda Greta (2016), T Cell Priming by Activated Nlrc5-Deficient Dendritic Cells Is Unaffected despite Partially Reduced MHC Class I Levels., in Journal of immunology (Baltimore, Md. : 1950), 196(7), 2939-46.
Btn2a2, a T cell immunomodulatory molecule coregulated with MHC class II genes.
Sarter Kerstin, Leimgruber Elisa, Gobet Florian, Agrawal Vishal, Dunand-Sauthier Isabelle, Barras Emmanuèle, Mastelic-Gavillet Béatris, Kamath Arun, Fontannaz Paola, Guéry Leslie, Duraes Fernanda do Valle, Lippens Carla, Ravn Ulla, Santiago-Raber Marie-Laure, Magistrelli Giovanni, Fischer Nicolas, Siegrist Claire-Anne, Hugues Stéphanie, Reith Walter (2016), Btn2a2, a T cell immunomodulatory molecule coregulated with MHC class II genes., in The Journal of experimental medicine, 213(2), 177-87.
Bare Lymphocyte Syndrome, Type I
de la SalleHenri, ReithWalter, Bare Lymphocyte Syndrome, Type I, Springer, USA.
Bare Lymphocyte Syndrome, Type II
ReithWakter, Bare Lymphocyte Syndrome, Type II, Springer, USA.

Collaboration

Group / person Country
Types of collaboration
Christoph Mueller, Bern Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
- Exchange of personnel
Stéphanie Hugues, Geneva Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
- Exchange of personnel
Proteomics core facility, Geneva Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Research Infrastructure
Marie-Laure Santiago Raber, Geneva Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Exchange of personnel
Bernd Wollscheid, Zurich Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
- Exchange of personnel
NovImmune SA, Geneva Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
- Exchange of personnel
Georg Hollander, Basel Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
- Exchange of personnel
Hans Acha-Orbea, Lausanne Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
- Exchange of personnel
Felix Meissner, Munich Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication

Associated projects

Number Title Start Funding scheme
144085 Regulation of antigen presentation and antigen presenting cell function 01.01.2013 Project funding
185375 Function and mode of action of BTN1A1 and BTN2A2, two novel immune checkpoint regulators 01.04.2019 Project funding

Abstract

Butyrophilins are cell-surface glycoproteins related to the B7 family of co-stimulatory molecules implicated in the regulation of T-cell responses. There is growing evidence that butyrophilins play diverse roles in the immune system. Our work on the regulation of MHC class II (MHCII) expression revealed that the gene encoding butyrophilin 2A2 (BTN2A2) is a target of the MHCII-specific transcription machinery. Human BTN2A2 and mouse Btn2a2 genes are regulated in antigen presenting cells (APCs), thymic epithelial cells (TECs) and IFN?-induced cells by regulatory factor X (RFX) and the class II transactivator (CIITA), two transcription factors dedicated for transcription of MHCII genes. The generation and analysis of Btn2a2-/- mice allowed us to provide conclusive genetic evidence that BTN2A2 functions as a co-inhibitory molecule that modulates T cell responses in vivo. The overall objectives of this project are to define the expression patterns, immunoregulatory functions and mechanisms of action of BTN2A2. Work will have 5 specific aims. Aim 1 is to characterize in detail the pattern of BTN2A2 expression in vivo under steady-state conditions in naïve mice, and during the course of adaptive immune responses. Aim 2 is to define in vivo functions of BTN2A2 by studying its role in TECs and thymocyte selection, and in shaping adaptive immune responses in the context of immunization, autoimmune diseases and tumor models. Aim 3 is to study conservation of the expression and function of BTN2A2 in humans. BTN2A2 expression by human tumors will also be assessed as it could, by analogy to other T cell inhibitory pathways, be implicated in escape from tumor immunosurveillance. Aim 4 is to identify the receptor(s) for BTN2A2 on T cells by three strategies, analysis of suspected candidates, using a novel ligand-based receptor-capture assay, and performing expression-cloning screens. Aim 5 is to characterize the “interactome” of BTN2A2, and its interaction partners in APCs, by using both affinity-purification and proximity labeling with biotin (BioID). These investigations are anticipated to fill major gaps in our knowledge on butyrophilin biology. They will in particular provide detailed insights on a new T cell co-inhibitory axis that could be of potential therapeutic relevance for the treatment of cancer or autoimmune diseases.
-