Antigen Presenting Cells in 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
The aim of vaccination is to generate memory cells endowed with enhanced or novel functional capacities capable of inducing an amplified and faster immune response to subsequent pathogen exposure. We postulate that fitness and quality of the humoral immunity conferred during an immune response rely on the manipulation of Dendritic cells (DC) that regulate Tfh and Tfr development, consequently germinal center (GC) reactions and, ultimately, the composition of the memory Tfh and B compartments.
Using specific antigen models that we have developed in the lab, our objectives are to evaluate: 1- the nature of the delivery system and the nature of the immunomodulatory signals that control these events, 2- the links between the anatomy of the memory compartments and memory fitness, 3- the influence of vaccine formulation on Ag availability and persistence, 4- the crosstalk between different memory cells that tightly collaborate during recall responses.
On one hand, we are assessing the impact of TLR and STING agonists alone or in combination in different delivery forms: lipidated, alum adsorbed, nanoparticles on the antigen-specific response and its protective effect to bacterial infection. On a second hand, our goal is also to circumvent vaccine hyporesponsiveness at extreme ages (neonatal and elderly). We plan on optimizing adjuvant formulation strategies that drive human Tfh cell differentiation.
One other aspect of our studies focuses on how Foxp3+ T cells regulate humoral responses. The output of the GC varies with the inflammatory context. Until now, such differences were attributed to the Tfh heterogeneity. However, we recently showed that T cell priming by DC also impacts the Tfr compartment, demonstrating that Tfr share many proprieties with Tfh such as antigen-specificity, polarization according to the inflammatory milieu and promotion of GC reaction. This suggests that the multifaceted function of Tfr may reflect the function of different cell subsets. In this context, we are deciphering the heterogeneity of the Tfr compartment and evaluating the physiological role of the different Tfr subsets in response to non-self antigen or during B cell-dependent encephalomyelitis.
Finally, it is now clear that the Tfh/B crosstalk controls reciprocally Tfh and B-cell plasticity. As such we demonstrated that BCR affinity conrols effector Tfh development. We also revealed that the memory maintenance and function after antigen re-encounter rely both on Tfh/B cognate interactions.
We now describe in depth memory Tfh cells and evaluate the physiological impact of these cell interactions on the quality and longevity of a humoral response in mouse and human settings. Moreover, we also study human autoimmune pathologies mediated by auto-antibodies such as Pemphigus vulgaris and assess how the response of patients to B-cell depleting treatment relies not only on the inhibition of the auto-reactive B cells but also on their cognate cell regulators, namely the Tfh cells.
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.
Aging Cell, 2021.
Proc Natl Acad Sci U S A, 117 (23), pp. 12969-12979, 2020.
Clin Transl Sci, 13 (3), pp. 529-538, 2020.
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J Prev Alzheimers Dis. , 7 (1), pp. 56-64, 2020.
J Clin Med, 9 (1), 2019.
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J Autoimmun., 94 , pp. 134-142, 2018, ISSN: 1095-9157.
Front Immunol. , 9 , pp. 2399 , 2018, ISSN: 1664-3224.
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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).
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Dendritic cells in tolerance and autoimmune diabetes Journal Article
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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
- General public conference at the University of Toulouse, ‘The vaccinal hesitation in France’, 2018
- Science in the City Festival, ESOF (EuroScience Open Forum), ‘Vaccination – Let’s talk about it’, 2018
- 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)