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Deciphering the differentiation and effector functions of the different B-cell subsets

from basic science:
  • immune response
  • antibodies
  • memory
to the translational research:
  • vaccination
  • auto-immunity
Claude-Agnès Reynaud
Jean-Claude Weill
Development of the immune system

Claude-Agnès Reynaud and Jean-Claude Weill got a PhD in molecular biology at the Institute Jacques Monod (Paris) in the team of K. Scherrer in 1981 and 1980. They then studied the generation of the antibody repertoire using the chicken model and discovered gene conversion as a generator of antibody diversity. They moved to the Basel Institute in 1987 where they further develop repertoire studies in the sheep model. In 1991, JCW was appointed Professor of Immunology at the Necker hospital, and CAR Director of Research at CNRS and started to study the development of the B cell compartment in mice and humans. Since 2010, JCW is Professor Emeritus.

Awards : CAR got the Silver Medal from CNRS (1991) and JCW is a member of the French Academy of Sciences (2011). They are both EMBO members and received an ERC Advanced grant, in 2010 and 2016, respectively

Focus

Understanding the functional diversity of B cell memory and effector subsets during immune responses in both mice and humans, as well as in human autoimmune diseases mediated by pathogenic antibodies.

Introduction

Most vaccines are based on antibodies and thus on the B cell arm of the immune system, but one still does not have a clear picture of the cellular and molecular basis of B cell memory. We have recently proposed, using a fate mapping mouse model, the concept of “multi-layered B cell memory response”, which implies that there are different memory B cell subsets with different effector functions engaged in a recall response. Nevertheless, the behavior of each B cell memory subset seems to vary depending on the model studied, i.e. on factors such as the type of antigen and adjuvant used and the timing of successive immune challenges. As an additional complexity, the human memory B cell compartment appears very different from the one of rodents in term of subsets and phenotypes. Improved vaccination strategies will therefore depend on a better understanding of what are the B cell subsets involved during responses against induced (vaccines) or natural (infection) antigenic challenges. Our project aims at addressing several of these questions and is developed along five axes.

Research objectives

  1. Long-term memory in humans: deciphering the molecular basis of life-long persistence.
    Based on the study of memory B cells against smallpox, we wish to determine whether long-lived memory B cells present a specific transcriptional program and a distinct cellular homeostasis.
  2. Marginal zone and IgM memory B cells in humans: two subsets with distinct effector functions and differentation/activation pathways?
    Our recent data suggest that IgM memory and marginal zone B cells represent two different subsets with distinct Ig repertoires. We will study their differential mobilization in an anti-pneumococcal response, their expression/activation profile and their ontogeny in a humanized mouse model.
  3. Immune thrombocytopenia (ITP), as a model for auto-immune diseases mediated by antibodies.
    We will take advantage of the therapeutic setting of splenectomy performed after B-cell depletion (rituximab) treatment failure to analyze, during relapse of the disease, what B-cell specificities (self-antigens, infectious agents) emerge in the various B cell subsets engaged in the active splenic immune response and whether it could give insight into the causes of the autoimmune process.
  4. An inducible fate-mapping mouse model to follow germinal center-derived TFH and memory B cells.
    An inducible Cre-ERT2 mouse model based on Bcl6 gene expression will allow us to follow how memory B and TFH cells persist and cooperate during a recall response, and whether TFH cells represent a stable lineage or can adopt multiple fates upon further challenges.
  5. The human ICF syndrome (Immunodeficiency, Centromeric instability and Facial dismorphism): can we get insight into the memory vs. plasma cell lineage choice taking place in germinal centers through the study of mouse models of this syndrome, a genetic disease caused by the inactivation of DNA methylation factors?

5 main publications

  • Mahévas, M., [...], Godeau, B., Michel, M., Weill, J.-C. and Reynaud, C.-A.
    B-cell depletion in immune thrombocytopenia reveals splenic long-lived plasma cells.
    J. Clin. Invest. 123, 432-442 (2013)
  • Descatoire, M., Weller, S., Irtan, S. [...], Weill, J.-C. and Reynaud, C.-A.
    Identification of a human splenic marginal zone B-cell precursor with NOTCH2-dependent differentiation properties.
    J. Exp. Med. 211, 987-1000 (2014)
  • Bagnara, D., [...], Weller, S., Dunn-Walters, D., Weill, J.C. and Reynaud, C.A.
    A reassessment of IgM memory subsets in humans.
    J. Immunol. 195, 3716-3724 (2015)
  • Girelli Zubani, G., Zivojnovic, M., [...], Weill, J.-C., Reynaud, C.-A. and Storck, S.
    PMS2 and uracil-DNA glycosylases act jointly in the mismatch repair pathway to generate Ig gene mutations at A-T base pairs.
    J. Exp. Med. 214, 1169-1180 (2017)
  • Le Gallou, S., Zhou, Z. [...], Weller, S., Weill, J.-C. and Reynaud, C.-A.
    A splenic IgM memory subset with anti-bacterial specificities is sustained from persistent mucosal responses
    J. Exp. Med. 215, 2035-2053 (2018)
Last 30 publications

2019

  • Weill, J.-C. and Reynaud, C.-A.
    IgM memory B cells: specific effectors of innate-like and adaptive responses.
    Curr. Opin. Immunol. 2019 Oct 19 [Epub ahead of print]
  • 2018

  • Thai, L.H., Le Gallou, S., Robbins, A., Crickx, E., Fadeev, T., Zhou Z, Cagnard N, Mégret, J., Bole, C., Weill, J.-C., Reynaud, C.-A. and Mahévas, M.
    BAFF and CD4+ T cells are major survival factors for long-lived splenic plasma cells in a B-cell-depletion context.
    Blood 131, 1545-1555 (2018)
  • Le Gallou, S., Zhou, Z. Thai, L.-H., Fritzen, R., Verge de los Aires, A., Mégret, J., Yu, P., Kitamura, D., Bille, E., Tros, F., Nassif, X., Charbit, A., Weller, S., Weill, J.-C. and Reynaud, C.-A.
    A splenic IgM memory subset with anti-bacterial specificities is sustained from persistent mucosal responses.
    J. Exp. Med. 215, 2035-2053 (2018)
  • Lino, A.C., Dang, V.D., Lampropoulou, V., Welle, A., Joedicke, J., Pohar, J., Simon, Q., Thalmensi, J., Baures, A., Fluher, V., Sakwa, I., Stervbo, U., Ries, S., Jouneau, L., Boudinot, P., Tsubata, T., Adachi, T., Hutloff, A., Dorner, T., Zimber-Strobl, U., de Vos, A.F., Dahlke, K., Loh, G., Korniotis, S., Goosmann, C., Weill, J.-C., Reynaud, C.-A., Kaufmann, S.H.E., Walter, J. and Fillatreau, S.
    LAG-3 inhibitory receptor expression identifies immunosuppressive natural regulatory plasma cells.
    Immunity 49, 120-133 (2018)
  • 2017

  • Girelli Zubani, G., Zivojnovic, M., De Smet, A., Albagli-Curiel, O., Huetz, F., Weill, J.-C., Reynaud, C.-A. and Storck, S.
    PMS2 and uracil-DNA glycosylases act jointly in the mismatch repair pathway to generate Ig gene mutations at A-T base pairs.
    J. Exp. Med. 214, 1169-1180 (2017)
  • Bertocci, B., Lecoeuche, D., Sterlin, D., Kühn, J., Gaillard, B., De Smet, A., Lembo, F., Bole-Feysot, C., Cagnard, N., Fadeev, T., Dahan, A., Weill, J.-C. and Reynaud, C.-A.
    Klhl6 deficiency impairs transitional B cell survival and differentiation.
    J. Immunol. 199, 2408-2420 (2017).
  • Degn, S.E., van der Poel, C.E., Firl, D.J., Ayoglu, B., Al Qureshah, F.A., Bajic, G., Mesin, L., Reynaud, C.-A., Weill, J.-C., Utz, P.J., Victora, G.D. and Carroll, M.C.
    Clonal Evolution of Autoreactive Germinal Centers.
    Cell 170, 913-926 (2017)
  • 2016

  • Fritzen R, Delbos F, De Smet A, Palancade B, Canman CE, Aoufouchi S, Weill JC, Reynaud CA, Storck S. A single aspartate mutation in the conserved catalytic site of Rev3L generates a hypomorphic phenotype in vivo and in vitro. DNA Repair (Amst). 2016 Oct;46:37-46.
  • Tas JM, Mesin L, Pasqual G, Targ S, Jacobsen JT, Mano YM, Chen CS, Weill JC, Reynaud CA, Browne EP, Meyer-Hermann M, Victora GD. Visualizing antibody affinity maturation in germinal centers. Science. 2016 Mar 4;351(6277):1048-54.
  • 2015

  • Weill JC, Reynaud CA. The ups and downs of negative (and positive) selection of B cells. J Clin Invest. 2015 Sep 14:1-3.
  • Bagnara D, Squillario M, Kipling D, Mora T, Walczak AM, Da Silva L, Weller S, Dunn-Walters DK, Weill JC, Reynaud CA. A Reassessment of IgM Memory Subsets in Humans. J Immunol. 2015 Sep 9. pii: 1500753. [Epub ahead of print]
  • Mahévas M, Michel M, Vingert B, Moroch J, Boutboul D, Audia S, Cagnard N, Ripa J, Menard C, Tarte K, Mégret J, Le Gallou S, Patin P, Thai L, Galicier L, Bonnotte B, Godeau B, Noizat-Pirenne F, Weill JC, Reynaud CA. Emergence of long-lived autoreactive plasma cells in the spleen of primary warm auto-immune hemolytic anemia patients treated with rituximab. J Autoimmun. 2015 Aug;62:22-30.
  • Blondelle J, Ohno Y, Gache V, Guyot S, Storck S, Blanchard-Gutton N, Barthélémy I, Walmsley G, Rahier A, Gadin S, Maurer M, Guillaud L, Prola A, Ferry A, Aubin-Houzelstein G, Demarquoy J, Relaix F, Piercy RJ, Blot S, Kihara A, Tiret L, Pilot-Storck F. HACD1, a regulator of membrane composition and fluidity, promotes myoblast fusion and skeletal muscle growth. J Mol Cell Biol. 2015 Oct;7(5):429-40.
  • Weller S, Descatoire M. [IgM+IgD+CD27+ B cells in human: an essential role in the protection against encapsulated bacteria]. Med Sci (Paris). 2015 Jun-Jul;31(6-7):647-53.
  • Aoufouchi S, De Smet A, Delbos F, Gelot C, Guerrera IC, Weill JC, Reynaud CA. 129-Derived Mouse Strains Express an Unstable but Catalytically Active DNA Polymerase Iota Variant.Mol Cell Biol. 2015 Sep 1;35(17):3059-70.
  • 2014

  • Weill JC, Reynaud CA. [Ever more humanized mice for new therapeutic applications]. Med Sci (Paris). 2014 Nov;30(11):949-51.
  • Zivojnovic M, Delbos F, Girelli Zubani G, Julé A, Alcais A, Weill JC, Reynaud CA, Storck S. Somatic hypermutation at A/T-rich oligonucleotide substrates shows different strand polarities in Ung-deficient or -proficient backgrounds. Mol Cell Biol. 2014 Jun;34(12):2176-87.
  • Descatoire M, Weller S, Irtan S, Sarnacki S, Feuillard J, Storck S, Guiochon-Mantel A, Bouligand J, Morali A, Cohen J, Jacquemin E, Iascone M, Bole-Feysot C, Cagnard N, Weill JC, Reynaud CA. Identification of a human splenic marginal zone B cell precursor with NOTCH2-dependent differentiation properties. J Exp Med. 2014 May 5;211(5):987-1000.
  • 2013

  • Mahévas M, Michel M, Weill JC, Reynaud CA. Long-lived plasma cells in autoimmunity: lessons from B-cell depleting therapy. Front Immunol. 2013 Dec 27;4:494.
  • Weill JC, Le Gallou S, Hao Y, Reynaud CA. Multiple players in mouse B cell memory. Curr Opin Immunol. 2013 Jun;25(3):334-8.
  • Mahévas M, Patin P, Huetz F, Descatoire M, Cagnard N, Bole-Feysot C, Le Gallou S, Khellaf M, Fain O, Boutboul D, Galicier L, Ebbo M, Lambotte O, Hamidou M, Bierling P, Godeau B, Michel M, Weill JC, Reynaud CA. B cell depletion in immune thrombocytopenia reveals splenic long-lived plasma cells. J Clin Invest. 2013 Jan;123(1):432-42.
  • 2012

  • Weller S, Bonnet M, Delagreverie H, Israel L, Chrabieh M, Maródi L, Rodriguez-Gallego C, Garty BZ, Roifman C, Issekutz AC, Zitnik SE, Hoarau C, Camcioglu Y, Vasconcelos J, Rodrigo C, Arkwright PD, Cerutti A, Meffre E, Zhang SY, Alcais A, Puel A, Casanova JL, Picard C, Weill JC, Reynaud CA. IgM+IgD+CD27+ B cells are markedly reduced in IRAK-4-, MyD88-, and TIRAP- but not UNC-93B-deficient patients. Blood. 2012 Dec 13;120(25):4992-5001.
  • Reynaud CA, Descatoire M, Dogan I, Huetz F, Weller S, Weill JC. IgM memory B cells: a mouse/human paradox. Cell Mol Life Sci. 2012 May;69(10):1625-34.
  • Permanent researcher
    Jean Davoust
    Researcher
    +33 (0)1 44 38 15 05
    Matthieu Mahevas
    Professor Researcher
    +33 (0)1 40 61 54 19
    Sébastien Storck
    -
    +33 (0)1 40 61 54 20
    Jean-Claude Weill
    Researcher
    +33 (0)1 40 61 64 47
    Sandra Weller
    Researcher
    +33 (0)1 40 61 54 20
    Permanent engineer
    Lucie Da Silva
    Assistant in Biological Techniques
    +33 (0)1 40 61 54 19
    Annie Desmet Barberi
    Engineer
    +33 (0)1 40 61 54 21
    Damiana Lecoeuche
    Technician
    +33 (0)1 40 61 54 21
    Non permanent engineer
    Tatiana Fadeev
    Engineer
    +33 (0)1 40 61 54 20
    Clara Goetz
    Engineer
    +33 (0)1 40 61 54 20
    Louise Pannetier
    Engineer
    +33 (0)1 40 61 54 20
    Akhésa Sochon
    Engineer
    +33 (0)1 40 61 54 21
    Post-doctoral degree
    Pascal Chappert
    Post-Doctoral Researcher
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    Viviana Valeri
    Post-Doctoral Researcher
    +33 (0)1 40 61 54 21
    PhD
    Clara Cousu
    PhD Student
    +33 (0)1 40 61 54 21
    Eléonore Mulot
    -
    +33 (0)1 40 61 54 21
    Aurélien Sokal
    PhD Student
    +33 (0)1 40 61 54 19
    Emeritus
    Claude-Agnès Reynaud
    -
    +33 (0)1 40 61 54 17
    Address

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    Support(s)
    HRH Princess Caroline of Hanover, who through the Princess Grace Foundation, already supports medical research and anything that helps to relieve the sick children in France and around the world, has agreed to commit to our side so that our Center of Molecular medicine continues to meet the current challenges and fight diseases, and in particular the ones affecting children.

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