Cellules présentatrices de l’antigène dans les réponses cellulaires T

Coordinators : N. Fazilleau / S. Guerder

Scientific objectives


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 are to determine how the function of DC are program during ontogeny and to examine how these cellular interactions between different antigen-presenting cells and T 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).

 

Our Projects


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.

Figpart2-1Using 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.

 

figpart2-2We 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.

Other informations


Publications

2021

Baumjohann, D; Fazilleau, N

Antigen-dependent multistep differentiation of T follicular helper cells and its role in SARS-CoV-2 infection and vaccination. Article de journal

Eur J Immunol., 2021.

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Martinez, F; Novarino, J; Mejía, J E; Fazilleau, N; Aloulou, M

Ageing of T-dependent B cell responses Article de journal

Immunology letters, 2021.

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Maho-Vaillant, M; Pérals, C; Golinski, ML; Hébert, V; Caillot, F; Mignard, C; Riou, G; Petit, M; Viguier, M; Hertl, M; Boyer, O; Calbo, S; Fazilleau, N; Joly, P

RITUXIMAB AND CORTICOSTEROID EFFECT ON DESMOGLEIN-SPECIFIC B-CELLS AND DESMOGLEIN-SPECIFIC T-FOLLICULAR-HELPER-CELLS IN PEMPHIGUS Article de journal

J. Invest Dermatol , 2021.

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Webb, LMC ; S, Fra-Bido; S, Innocentin; LS, Matheson; N, Attaf; A, Bignon; J, Novarino; N, Fazilleau; MA., Linterman

Ageing promotes early T follicular helper cell differentiation by modulating expression of RBPJ Article de journal

Aging Cell, 2021.

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2020

G, Blaize; H, Daniels-Treffandier; M, Aloulou; N, Rouquié; C, Yang; M, Marcellin; M, Gador; M, Benamar; M, Ducatez; KD, Song; O, Burlet-Schiltz; A, Saoudi; PE, Love; N, Fazilleau; de A, Gonzalez Peredo; R., Lesourne

CD5 signalosome coordinates antagonist TCR signals to control the generation of Treg cells induced by foreign antigens. Article de journal

Proc Natl Acad Sci U S A, 117 (23), p. 12969-12979, 2020.

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F, Briand; C, Heymes; L, Bonada; T, Angles; J, Charpentier; M, Branchereau; E, Brousseau; M, Quinsat; N, Fazilleau; R, Burcelin; T., Sulpice

A 3-week nonalcoholic steatohepatitis mouse model shows elafibranor benefits on hepatic inflammation and cell death. Article de journal

Clin Transl Sci, 13 (3), p. 529-538, 2020.

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K, Mahiddine; C, Hassel; C, Murat; M, Girard; S., Guerder

Tissue-Specific Factors Differentially Regulate the Expression of Antigen-Processing Enzymes During Dendritic Cell Ontogeny. Article de journal

Front Immunol. , 11 (453), 2020.

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F, Guerville; De Souto Barreto P, ; I, Ader; S, Andrieu; L, Casteilla; C, Dray; N, Fazilleau; S, Guyonnet; D, Langin; R, Liblau; A, Parini; P, Valet; N, Vergnolle; Y, Rolland; B., Vellas

Revisiting the Hallmarks of Aging to Identify Markers of Biological Age. Article de journal

J Prev Alzheimers Dis. , 7 (1), p. 56-64, 2020.

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2019

C, Dubois; F, Martin; C, Hassel; F, Magnier; P, Daumar; C, Aubel; S, Guerder; E, Mounetou; F, Penault-Lorca; M., Bamdad

Low-Dose and Long-Term Olaparib Treatment Sensitizes MDA-MB-231 and SUM1315 Triple-Negative Breast Cancers Spheroids to Fractioned Radiotherapy. Article de journal

J Clin Med, 9 (1), 2019.

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M, Aloulou; N., Fazilleau

Regulation of B cell responses by distinct populations of CD4 T cells. Article de journal

Biomed J. , 42 (4), p. 243-251, 2019.

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Guerder, S; Hassel, C; Carrier, A

Thymus-specific serine protease, a protease that shapes the CD4 T cell repertoire. Article de journal

Immunogenetics, 71 (3), p. 223, 2019.

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2018

Nguyen, XH. ; Dauvilliers, Y; Quériault, C; Pérals, C; Romieu-Mourez, R; Paulet, PE. ; Bernard-Valnet, R; Fazilleau, N; Liblau, R

Circulating follicular helper T cells exhibit reduced ICOS expression and impaired function in narcolepsy type 1 patients. Article de journal

J Autoimmun., 94 , p. 134-142, 2018, ISSN: 1095-9157.

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Bernard, I; Sacquin, A; Kassem, S; Benamar, M; Colacios, C; Gador, M; Pérals, C; Fazilleau, N; Saoudi, A

A Natural Variant of the Signaling Molecule Vav1 Enhances Susceptibility to Myasthenia Gravis and Influences the T Cell Receptor Repertoire. Article de journal

Front Immunol. , 9 , p. 2399 , 2018, ISSN: 1664-3224.

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Fazilleau, N; Aloulou, M

Several Follicular Regulatory T Cell Subsets With Distinct Phenotype and Function Emerge During Germinal Center Reactions. Article de journal

Front Immunol. , 9 , p. 1792, 2018, ISSN: 1664-3224.

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2017

Asrir, A; Aloulou, M; Gador, M; Perals, C; Fazilleau, N

Interconnected subsets of memory follicular helper T cells have different effector functions Article de journal

Nat Commun, 8 (1), p. 847, 2017, ISSN: 2041-1723 (Electronic) 2041-1723 (Linking).

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Sacquin, A; Gador, M; Fazilleau, N

The strength of BCR signaling shapes terminal development of follicular helper T cells in mice Article de journal

Eur J Immunol, 47 (8), p. 1295-1304, 2017, ISSN: 1521-4141 (Electronic) 0014-2980 (Linking).

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Serre, L; Girard, M; Ramadan, A; Menut, P; Rouquie, N; Lucca, L E; Mahiddine, K; Leobon, B; Mars, L T; Guerder, S

Thymic-Specific Serine Protease Limits Central Tolerance and Exacerbates Experimental Autoimmune Encephalomyelitis Article de journal

Journal of Immunology, 199 (11), p. 3748-3756, 2017, ISSN: 0022-1767.

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2016

Aloulou, M; Carr, E J; Gador, M; Bignon, A; Liblau, R S; Fazilleau, N; Linterman, M A

Follicular regulatory T cells can be specific for the immunizing antigen and derive from naive T cells Article de journal

Nat Commun, 7 , p. 10579, 2016, ISSN: 2041-1723 (Electronic) 2041-1723 (Linking).

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Joncker, N T; Bettini, S; Boulet, D; Guiraud, M; Guerder, S

The site of tumor development determines immunogenicity via temporal mobilization of antigen-laden dendritic cells in draining lymph nodes Article de journal

European Journal of Immunology, 46 (3), p. 609-618, 2016, ISSN: 0014-2980.

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2015

Viret, C; Mahiddine, K; Baker, R L; Haskins, K; Guerder, S

The T Cell Repertoire-Diversifying Enzyme TSSP Contributes to Thymic Selection of Diabetogenic CD4 T Cell Specificities Reactive to ChgA and IAPP Autoantigens Article de journal

J Immunol , 5 (195), p. 1964-1973, 2015.

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Chakarov, S; Fazilleau, N

Tracking by flow cytometry antigen-specific follicular helper T cells in wild-type animals after protein vaccination Article de journal

Methods Mol Biol, 1291 , p. 39-47, 2015, ISSN: 1940-6029 (Electronic) 1064-3745 (Linking).

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Serre, L; Fazilleau, N; Guerder, S

Central tolerance spares the private high-avidity CD4 T-cell repertoire specific for an islet antigen in NOD mice Article de journal

Eur J Immunol, 2015, ISSN: 1521-4141 (Electronic) 0014-2980 (Linking).

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2014

Chakarov, S; Fazilleau, N

Monocyte-derived dendritic cells promote T follicular helper cell differentiation Article de journal

EMBO Mol Med, 6 , p. 590-603, 2014, ISSN: 1757-4684 (Electronic) 1757-4676 (Linking).

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2013

Guerder, S; Joncker, N; Mahiddine, K; Serre, L

Dendritic cells in tolerance and autoimmune diabetes Article de journal

Curr Opin Immunol, 25 (6), p. 670-5, 2013, ISSN: 1879-0372 (Electronic) 0952-7915 (Linking).

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2012

Guerder, S; Viret, C; Luche, H; Ardouin, L; Malissen, B

Differential processing of self-antigens by subsets of thymic stromal cells Article de journal

Curr Opin Immunol, 24 (1), p. 99-104, 2012, ISSN: 1879-0372 (Electronic) 0952-7915 (Linking).

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2011

Viret, C; Leung-Theung-Long, S; Serre, L; Lamare C.and Vignali, D.A.and Malissen B; Carrier, A; Guerder, S

Thymus-specific serine protease controls autoreactive CD4 T cell development and autoimmune diabetes in mice. Article de journal

J Clin Invest , 121 (5), p. 1810-1821, 2011.

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Viret, C; Lamare, C; Guiraud, M; Fazilleau, N; Bour, A; Malissen, B; Carrier, A; Guerder, S

Thymus-specific serine protease contributes to the diversification of the functional endogenous CD4 T cell receptor repertoire. Article de journal

J Exp Med., 208 , p. 3-11, 2011.

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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:

Alumni

Graduate Students:

  • Mario De la Fuenet (06/2020-07/2020)

  • Adrienne Forgue-Meyre (01/2020-03/2020)

  • Olivia Paronetto (01/2020-03/2020)

  • Audrey Turban (01/2020-03/2020)

  • Sebastien Dealmeida (03/2018-04/2018)

  • Lucie Robert (11/2018-12/2018)

  • Nelly Pourteau (02/2018-03/2018)
  • Cyrine Chanchabi (11/2017-01/2018)
  • Laureline Ratzel (05/2017-06/2017)
  • Flore Lebrun (11/2015-01/2016)
  • Kim Pacchiardi (11/2014-01/2015)
  • Thomas Genais (11/2013-01/2014)
  • Marie-Adélaïde Cucchi (11/2012-01/2013)
  • Suzanne Faure (11/2012-01/2013)
  • Regis Joulia (11/2011-01/2012)
  • Marine Vinel (11/2011-01-2012)
  • Laure Garnier (01/2011-03/2011)

 

 Master Students:

  • 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)

 

PhD Students:

  • 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 svetoslav_chakarov@immunol.a-star.edu.sg
  • Assia Asrir, (09/2010-10/2015), PhD Defense 15/07/2015
    Now Post-doc in JP Girard’s Lab, IPBS, Toulouse, France
    assia.asrir@ipbs.fr
  • Laurent Serre (09/2010-01/2015), PhD Defense29/01/2015
    Now Post-doc in A. Puissieux’s Lab, CRCL, Lyon, France

 

Post-Doctoral Fellow:

  • 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

Researcher:

  • Christophe Viret (05/2006-09/2012)
    Now at CIRI, Lyon, France
    Christophe.viret@inserm.fr

Research Assistants:

  • 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) Now technician at EVOTEC, Immuno-oncology team, Toulouse, France
  • Mylène Gador (01/2013-09/2018) Now technician at EVOTEC, Immuno-oncology team, Toulouse, France
  • 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) Now retired

 

 

 

 

 

 

Collaborations

Ellen Robey, University of California Berkeley, CA, USA

Michel Cogné, CNRS UMR 7276, Limoges, France

Thierry Defrance, CIRI, Lyon, France

Marie-Lise Gougeon, Institut Pasteur, Paris, France

Julie Heft, Institut Curie, INSERM U932, Paris France

Pascal Joly, Hopital de Rouen, France

David Klatzmann, U959 INSERM/Sorbonne University, Paris, France

Yasmina Laouar, University of Michigan, Ann Arbor, MI, USA.

Agnes Lehuen, Institut Cochin, Paris, France

Michelle Linterman, Babraham Institute, Cambridge, UK

Ludovic Martinet, CRCT, Toulouse, France

Karin Tarte, INSERM U917, Rennes, France

Manuelle Viguier, CHU de Reims, Paris, France

Bruno Vellas, Gérontopole Toulouse, France

 

 

 

 

 

 

 

ANRS

ANRS

EFSD

EFSD

Fondation de recherche médicale

Fondation de recherche médicale

Institut National Du Cancer

Institut National Du Cancer

JDFR

JDFR

Les actions marie sklodowska curie

Les actions marie sklodowska curie

INSERM

INSERM

CNRS

CNRS

ARSEP

ARSEP

Fondation de recherche médicale

Fondation de recherche médicale

Ligue contre le cancer

Ligue contre le cancer

Fondation ARC

Fondation ARC

Seventh Framework Programme

Seventh Framework Programme

Région Occitanie

Région Occitanie

Société Française de Dermatologie

Société Française de Dermatologie

Université Paul Sabatier

Université Paul Sabatier