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Function and mode of action of BTN1A1 and BTN2A2, two novel immune checkpoint regulators

English title Function and mode of action of BTN1A1 and BTN2A2, two novel immune checkpoint regulators
Applicant Hugues Stéphanie
Number 185375
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 01.04.2019 - 30.09.2020
Approved amount 444'761.00
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All Disciplines (2)

Discipline
Immunology, Immunopathology
Molecular Biology

Keywords (3)

tumour immunology; immune checkpoint regulators; Butyrophilins

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 deux nouvelles protéines, appelées BTN1A1 et BTN2A2, qui agissent comme des freins sur les réponses immunes chez la souris. Elle atténuent 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 immunorégulatrices de BTN1A1 et BTN2A2.
Lay summary

Les objectifs principaux de nos recherches portant sur les molécules BTN1A1 et BTN2A2 sont d'étudier l'expression de BTN1A1 et BTN2A2 in vivo, d'évaluer l'importance de BTN1A1 et BTN2A2 dans la régulation de différents types de réponses immunes normales et pathologiques, d’élucider les mécanismes cellulaires et moléculaires par le biais desquels BTN1A1 et BTN2A2 inhibent les réponses immunes, de déterminer si ces mécanismes sont conservés chez l’homme, et d'investiguer la possibilité que ces nouvelles voies immunorégulatrices pourraient constituer des nouvelles cibles thérapeutique pour des maladies impliquant les réponses immunitaires. Ces études apporteront de nouvelles connaissances fondamentales sur le fonctionnement du système immunitaire. Elles permettront notamment de mieux comprendre des nouvelles voies de régulation des réponses immunes. Nos recherches permettront également de déterminer si ces nouvelles voies de régulation pourraient être exploitées dans des buts thérapeutiques chez l'homme, notamment pour traiter des maladies autoimmunes ou pour renforcer des réponses immunes dirigées contre des cancers.

Direct link to Lay Summary Last update: 30.03.2019

Responsible applicant and co-applicants

Employees

Publications

Publication
Interplay of RFX transcription factors 1, 2 and 3 in motile ciliogenesis
Lemeille Sylvain, Paschaki Marie, Baas Dominique, Morlé Laurette, Duteyrat Jean-Luc, Ait-Lounis Aouatef, Barras Emmanuèle, Soulavie Fabien, Jerber Julie, Thomas Joëlle, Zhang Yong, Holtzman Michael J, Kistler W Stephen, Reith Walter, Durand Bénédicte (2020), Interplay of RFX transcription factors 1, 2 and 3 in motile ciliogenesis, in Nucleic Acids Research, 48(16), 9019-9036.
Specific enhancer selection by IRF3, IRF5 and IRF9 is determined by ISRE half-sites, 5′ and 3′ flanking bases, collaborating transcription factors and the chromatin environment in a combinatorial fashion
Csumita Mária, Csermely Attila, Horvath Attila, Nagy Gergely, Monori Fanny, Göczi Loránd, Orbea Hans-Acha, Reith Walter, Széles Lajos (2020), Specific enhancer selection by IRF3, IRF5 and IRF9 is determined by ISRE half-sites, 5′ and 3′ flanking bases, collaborating transcription factors and the chromatin environment in a combinatorial fashion, in Nucleic Acids Research, 48(2), 589-604.
Macrophage migration inhibitory factor regulates TLR4 expression and modulates TCR/CD3-mediated activation in CD4+ T lymphocytes
Alibashe-Ahmed Mohamed, Roger Thierry, Serre-Beinier Veronique, Berishvili Ekaterine, Reith Walter, Bosco Domenico, Berney Thierry (2019), Macrophage migration inhibitory factor regulates TLR4 expression and modulates TCR/CD3-mediated activation in CD4+ T lymphocytes, in Scientific Reports, 9(1), 9380-9380.
Mitochondrial arginase-2 is a cell‑autonomous regulator of CD8+ T cell function and antitumor efficacy
Líndez Adrià-Arnau Martí, Dunand-Sauthier Isabelle, Conti Mark, Gobet Florian, Núñez Nicolás, Hannich J. Thomas, Riezman Howard, Geiger Roger, Piersigilli Alessandra, Hahn Kerstin, Lemeille Sylvain, Becher Burkhard, De Smedt Thibaut, Hugues Stéphanie, Reith Walter (2019), Mitochondrial arginase-2 is a cell‑autonomous regulator of CD8+ T cell function and antitumor efficacy, in JCI Insight, 4(24), 1-21.
Toll-like receptor 4 inhibition prevents autoimmune diabetes in NOD mice
Alibashe-Ahmed Mohamed, Brioudes Estelle, Reith Walter, Bosco Domenico, Berney Thierry (2019), Toll-like receptor 4 inhibition prevents autoimmune diabetes in NOD mice, in Scientific Reports, 9(1), 19350-19350.

Associated projects

Number Title Start Funding scheme
166371 Expression, function and mechanism of action of BTN2A2, a new costimulatory molecule coregulated with MHC class II expression 01.04.2016 Project funding

Abstract

Butyrophilins are transmembrane glycoproteins for which diverse roles in the immune system have emerged over recent years. We recently reported that Butyrophilin-2A2 (BTN2A2) functions as a new inhibitory immune checkpoint regulator that dampens T effector cell (Th1, Th2, TH17) responses and promotes regulatory T cell (Treg) responses, in a manner reminiscent of the benchmark PDL1-PD1 pathway. During the previous grant period we generated a major amount of new unpublished data on the expression, function and mode of action of BTN2A2. We have notably generated extensive data on the role of BTN2A2 versus PDL1 as an immune checkpoint regulator in the context of anti-tumour responses, revealed a similar albeit distinct role of the related family member BTN1A1 in anti-tumour responses, defined a key role of BTN2A2 expression by B cells in regulating Th cell responses, and identified candidate receptors for BTN2A2. The current proposal aims to strengthen, consolidate and complete these findings. Work will have 5 specific aims. Aims 1 and 2 are to define the respective roles of BTN1A1 and BTN2A2 by studying immune responses in BTN1A1-deficient, BTN2A2-deficient and our newly generated BTN1A1/BTN2A2 double-knockout mice. Aim 3 is to further our understanding of the role of BTN2A2 expression by B cells. Aim 4 is to compare the molecular mechanisms mediating the differential inhibitory effects of BTN1A1, BTN2A2 and PDL1 on T cells. Aim 5 is to follow up and validate the candidate BTN2A2 receptors we have identified. These investigations should clarify the functions and mode of action of BTN2A2 and BTN1A1, and define their potential as novel therapeutic targets for immunotherapy.
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