Antigen Presenting Cells and CD4 T cell responses

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 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).

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

To get more insights into the molecular and cellular mechanisms behind humoral responses, we examine the heterogeneity of Tfh cells in vivo.

Figpart2-1 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.

figpart2-2

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.

Other informations


Publications

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. Journal Article

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

Links | BibTeX

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. Journal Article

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

Links | BibTeX

Guerder, S; Hassel, C; Carrier, A

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

Immunogenetics. , 2018.

Links | BibTeX

Fazilleau, N; Aloulou, M

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

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

Links | BibTeX

2017

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

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

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

Links | BibTeX

Sacquin, A; Gador, M; Fazilleau, N

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

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

Links | BibTeX

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 Journal Article

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

Links | BibTeX

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 Journal Article

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

Links | BibTeX

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 Journal Article

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

Links | BibTeX

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 Journal Article

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

Links | BibTeX

Chakarov, S; Fazilleau, N

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

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

Links | BibTeX

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 Journal Article

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

Links | BibTeX

2014

Chakarov, S; Fazilleau, N

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

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

Links | BibTeX

2013

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

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).

Links | BibTeX

2012

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

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

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

Links | BibTeX

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. Journal Article

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

Links | BibTeX

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. Journal Article

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

Links | BibTeX

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

  • 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)

 

Master’s Students

  • Claire Murat (2017-2018)
  • Céline Leroy (09/2006-06/2007)
  • Delphine Payros (09/2009-06/2010)
  • Sophie Papot (09/2009-06/2010)
  • Sarah Bettini (09/2011-06/2012)
  • Jennifer Series (01/2013-06/2013)
  • Marina Marcaud (01/2013-06/2013)
  • Edi Tihic (01/2014-06/2014)
  • Chloe Nobis (01/2014-06/2014)
  • Alba Verge de los Aires (01/2015-06/2015)
  • Alison Charton (01/2016-06/2016)
  • Thibault Angles (01/2017-06/2017)

 

PhD Students

  • Maeva Girard (     -2018). PhD Defense 27/09/2018 . Now in University Toulouse
  • Delphine Boulet (           ), PhD Defense    .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), Thesis defense 29/01/2015
    Now Post-doc in A. Puissieux’s Lab, CRCL, Lyon, France

 

Post-Doctoral Fellow

  • 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 Assistant

  • Jérémy Kagan (10/2009-12/2012)
    Now technician at EVOTEC, Immuno-oncology team, Toulouse, France
    Jeremy.Kagan@evotec.com
  • Audrey Tourdes (11/2010-12/2011)
  • Nelly Rouquié (11/2014-12/2015)
    Now AI INSERM at CPTP, Toulouse, France
    nelly.rouquie@inserm.fr
  • Martine Guiraud (12/2007-12/2015)
    Now retired

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