Antigen Presenting Cells and CD4 T cell responses
Coordinators : N. Fazilleau / S. Guerder
Antigen presenting cells, whether dendritic cells (DC), B cells or monocytes are critical regulators of immune responses. Hence, the functional program of the antigen-presenting will determine whether T cell tolerance or protective immunity is induced. The main focus of our team is to examine how these cellular interactions between antigen-presenting cells and T Helper cells impact immune responses in physiological or pathological contexts. We thus examine the mechanisms that regulate DC function to either induce T cell tolerance in autoimmune context or appropriate immune response for vaccine development or for the development of antitumor responses. We also examine how antigen-presenting cell-derived factors may contribute to the development of effector and memory T cells with a particular focus on the regulators of B cell immunity, T Follicular Helper cells (Tfh) and T Follicular regulatory cells (Tfr).
AXIS 1: Dendritic cells in central tolerance and autoimmunity
DC are major contributors to T cell tolerance.
In the thymus, the different DC subsets constitutively process and present peptides derived from self-proteins to developing thymocytes to induce either deletion of the self-reactive thymocytes or regulatory T cell development. Our team has uncovered the unique properties of the thymus specific serine protease (TSSP) in editing the “self” peptide repertoire presented by stromal cells in the thymus and its impact on the development of the auto-reactive T cell repertoire. Hence we showed that lack of TSSP expression by thymic DC enhances deletion of self-reactive CD4 T cells and thus prevents type 1 diabetes or reduces the severity of experimental autoimmune encephalomyelitis. In continuation, we further characterize TSSP function and assess new strategies based on the unique properties of TSSP for the treatment of these T cell-mediated autoimmune diseases.
Finally, by combining genome wide studies and functional studies we examine how the thymic environment condition thymic DC differentiation and maturation and endowed the thymic DC with constitutive antigen presenting function.
AXIS 2: Physiology, anatomy and regulation of T-dependent B cell responses
To get more insights into the molecular and cellular mechanisms behind humoral responses, we examine the heterogeneity of Tfh cells in vivo.
More precisely, we decipher the molecular mechanisms including the genetic and epigenetic programs that control this lineage. We also characterize this heterogeneity at the cellular and functional levels in the effector and memory phase. Finally, we assess how distinct populations of regulatory Foxp3+ T cells regulate humoral responses at priming and during their course in physiological and autoimmune context.
AXIS 3: Development of anti-tumor T cell responses
On one hand, we explore how the molecular interactions during the B-Tfh crosstalk participate to lymphomagenesis in the context of follicular and angio-immunoblastic lymphoma in order to discover new therapeutic targets.
On the other hand, we assess the mechanisms promoting or inhibiting DC recruitment and function within tumors. We recently showed that the site of tumor development determine tumor immunogenicity which relates to the kinetic of antigen-laden DC recruitment in draining lymph nodes. We now characterize the route and impact of the tumor environment on DC recruitment within tumors and define the molecular mechanisms involved using established live 2-photon imaging of tumor explants. Our long-term objective is to determine whether the factors that improve DC recruitment within tumors also promote DC recruitment in draining lymph nodes and, consequently, protective T cell response. In parallel, by combining genomic and functional studies, we study how the tumor environment modifies the function of DCs in tumors in order to identify factors allowing to reprogram them and to induce protective antitumor responses.
Thymus-specific serine protease, a protease that shapes the CD4 T cell repertoire. Journal Article
Immunogenetics, 71 (3), pp. 223, 2019.
J Autoimmun., 94 , pp. 134-142, 2018, ISSN: 1095-9157.
Front Immunol. , 9 , pp. 2399 , 2018, ISSN: 1664-3224.
Front Immunol. , 9 , pp. 1792, 2018, ISSN: 1664-3224.
Nat Commun, 8 (1), pp. 847, 2017, ISSN: 2041-1723 (Electronic) 2041-1723 (Linking).
Eur J Immunol, 47 (8), pp. 1295-1304, 2017, ISSN: 1521-4141 (Electronic) 0014-2980 (Linking).
Journal of Immunology, 199 (11), pp. 3748-3756, 2017, ISSN: 0022-1767.
Nat Commun, 7 , pp. 10579, 2016, ISSN: 2041-1723 (Electronic) 2041-1723 (Linking).
European Journal of Immunology, 46 (3), pp. 609-618, 2016, ISSN: 0014-2980.
J Immunol , 5 (195), pp. 1964-1973, 2015.
Methods Mol Biol, 1291 , pp. 39-47, 2015, ISSN: 1940-6029 (Electronic) 1064-3745 (Linking).
Eur J Immunol, 2015, ISSN: 1521-4141 (Electronic) 0014-2980 (Linking).
EMBO Mol Med, 6 , pp. 590-603, 2014, ISSN: 1757-4684 (Electronic) 1757-4676 (Linking).
Dendritic cells in tolerance and autoimmune diabetes Journal Article
Curr Opin Immunol, 25 (6), pp. 670-5, 2013, ISSN: 1879-0372 (Electronic) 0952-7915 (Linking).
Curr Opin Immunol, 24 (1), pp. 99-104, 2012, ISSN: 1879-0372 (Electronic) 0952-7915 (Linking).
J Clin Invest , 121 (5), pp. 1810-1821, 2011.
J Exp Med., 208 , pp. 3-11, 2011.
Impact on the society
Our work mainly focuses on how antigen presenting cells and antigen presentation impact CD4 T cell selection, or activation and survival in physiological or pathological context such as cancer or autoimmune diseases. We strongly believe that innovation towards the development of novel therapeutics can only stem from basic knowledge of outstanding quality that, ultimately, could translate into new therapeutic strategies.
Our philosophy is also to provide an optimal environment for the training of young scientists through the daily interaction with students working in our laboratory. A scientific project is attributed to each team member. Every member of the team receives training on all aspects covered by the general project. We ensure that all team members are aware of the strategies of the team and the host institute to manage the local research. All team members are strongly encouraged to write their own papers and meeting abstracts. The team members benefit from this training scheme in terms of further career prospects. All team members are encouraged to grow into independent investigators to different extents depending on their seniority.
Finally, we inform the general public about our scientific findings. The general public is made aware of our scientific advances via the public relations and communication service of the INSERM in Toulouse. We have already communicated our scientific endeavors to the local and national press using this service as shown below:
- Dépêche du Midi 2010
- La nuit des chercheurs 2011
- Ma thèse en 180 secondes 2015
- PhD Corner 2015
- Prix Charles Grupper 2015
- Lucie Robert (11/2018-12/2018)
- Cyrine Chanchabi (11/2017-01/2018)
- Laureline Ratzel (05/2017-06/2017)
- Nelly Pourteau (2017-2018)
- Sebastien Dealmeida (2017-2018)
- Laure Garnier (01/2011-03/2011)
- Marine Vinel (11/2011-01-2012)
- Regis Joulia (11/2011-01/2012)
- Marie-Adélaïde Cucchi (11/2012-01/2013)
- Suzanne Faure (11/2012-01/2013)
- Thomas Genais (11/2013-01/2014)
- Kim Pacchiardi (11/2014-01/2015)
- Flore Lebrun (11/2015-01/2016)
- Nelly Pourteau (09/2018-06/2019)
- Claire Murat (09/2017-06/2018)
- Thibault Angles (01/2017-06/2017)
- Alison Charton (01/2016-06/2016)
- Maeva Girard (09/2015-06/2016)
- Alba Verge de los Aires (01/2015-06/2015)
- Chloe Nobis (01/2014-06/2014)
- Edi Tihic (01/2014-06/2014)
- Jennifer Series (01/2013-06/2013)
- Marina Marcaud (01/2013-06/2013)
- Sarah Bettini (09/2011-06/2012)
- Laurent Serre (09/2009-06/2010)
- Delphine Payros (09/2009-06/2010)
- Sophie Papot (09/2009-06/2010)
- Céline Leroy (09/2006-06/2007)
- Maeva Girard ( 09/2016-09/2018). PhD Defense 27/09/2018 . Now in University Toulouse
- Delphine Boulet (11/2015-11/2017). PhD Defense 22/11/2017. Now Post Doc Centre GIGA, Liège, Belgique
- Svetoslav Chakarov (09/2009-12/2013), PhD Defense 19/12/2013
now Post-doc in Florent Ginhoux’s lab, Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Singapore
- Assia Asrir, (09/2010-10/2015), PhD Defense 15/07/2015
Now Post-doc in JP Girard’s Lab, IPBS, Toulouse, France
- Laurent Serre (09/2010-01/2015), Thesis defense 29/01/2015
Now Post-doc in A. Puissieux’s Lab, CRCL, Lyon, France
- Dr Chervin Hassel (09/2016-06/2018). Now Post Doc ENVT, Toulouse
- Dr Karim Mahiddine (09/2011-08/2013). Now Post Doc UCSF, CA USA
- Dr Nathalie Joncker (02/2010-08/2013). Now Science writer at InvivoGen Europe, Toulouse
- Dr Antoine Sacquin (01/2011-05/2015)
- Dr. Stéphane Leung-Theung-Long (09/2005-07/2010)
Now Scientific coordinator at Transgene, Lyon, France
- Christophe Viret (05/2006-09/2012)
Now at CIRI, Lyon, France
- Renaud Batrin (02/2015-11/2018). Now AI CNRS INSERM U944-CNRS UMR7212 Hopital Saint Louis, Paris, France
- Alison Charton (09/2016-05/2018)
- Marie Best (09/2018-06/2019)
- Mylène Gador (01/2013-09/2018)
- Jérémy Kagan (10/2009-12/2012)
Now technician at EVOTEC, Immuno-oncology team, Toulouse, France
- Audrey Tourdes (11/2010-12/2011)
- Nelly Rouquié (11/2014-12/2015)
Now AI INSERM at CPTP, Toulouse, France
- Martine Guiraud (12/2007-12/2015)