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T cell Differentiation and physiology of the memory response

from basic science:
  • homeostasis
  • hematopoiesis
to the translational research:
  • autoimmune diseases
  • transplantation
  • immunodeficiency
  • cancer
Sophie Ezine
Flora Zavala
Lymphopoiesis and immunoregulatory hematopoietic progenitors

Sophie Ezine: I earned my PhD degree from the University Paris 6 (UPMC) and then performed a postdoctoral fellowship. I trained at the department of Pathology (Stanford Medical center, USA) with Pr Irving L. Weissman. From then I became interested in T cells and more specifically, their origin. My scientific domains are: hematopoietic stem cell transplantation and T cell commitment, T cell differentiation and migration of bone-marrow progenitors to the thymus.

Flora Zavala: I earned my PhD degree from Paris 11 University and then performed my post-doctoral training at the department of medicinal chemistry of Kyoto University, Japan, with Pr. Osamu Hayaishi. From then, I became interested in immunology and particularly neuroimmunology. My present scientific domains are focused on the role of hematopoietic growth factors and progenitors in the regulation of autoimmune and allogeneic immune responses.

Focus

  • Molecular and cellular mechanisms of T cell commitment (S. Ezine)
  • ILC3 ontogeny and homeostasis (M. Cherrier)
  • Regulatory functions of hematopoietic progenitor sub-populations emerging in adaptive hematopoiesis (F Zavala)
  • Circulating rare cancer cells (P. Paterlini-Brechot)

Introduction

At the apex of the hematopoietic hierarchy, hematopoietic stem cells (HSCs) self-renew to maintain lifelong hematopoiesis. As HSCs differentiate, they upregulate Flt3 cytokine receptor expression to generate non-renewing multipotent progenitors (MPPs). The identification of downstream developmentally restricted progenitors, such as IL-7Rαhi common lymphoid progenitors (CLPs) established that development of related cell lineages proceeded via lineage-restricted intermediates. The mechanism by which some descendants of HSCs differentiate into lymphoid progenitors is not well understood but may involve signals from the bone marrow niche, cytokines, and transcription factors (SE).

Recent studies in mice and humans have significantly expanded the lymphocyte family from adaptive lymphocytes and NK cells to include several additional innate lymphoid cell (ILC) types. Much evidence supports the derivation of ILCs and T cells from lymphoid progenitors. Adoptive transfer experiments have shown that LMPPs and CLPs generate not only T and B cells, but also ILCs (MC). The possible feed-back control on immune responses of hematopoietic progenitor sub-populations emerging in adaptive hematopoiesis taking place in infectious and inflammatory conditions also warrants further investigation (FZ).

Finally, the study of rare circulating cells is implemented for the detection of foetal cells for non-invasive prenatal diagnostics of trisomy 21, and detection of circulating cancer cells, whose propagation in blood represents a key step in the metastasis formation process (PPB).

Research objectives

S. Ezine

BM transplants are expected to ensure continuous blood cell production in patients with hematological diseases and to correct congenital defects or acquired autoimmune disorders. The choice of cells to be transplanted is of major importance. Multipotent precursors from the bone marrow (BM) home to the thymic environment, which induces their entry into the T-lineage program. In the objectives to identify the early thymic events following BM grafts, in vivo and in vitro approaches associated with molecular analysis are performed.

M. Cherrier

RORγt+ innate lymphoid cells (ILC3) play a fundamental role in the development of lymphoid tissues as well as in the homeostasis and defense of mucosal tissues. Deregulation of ILC3 is associated with inflammatory pathology. Our first aim is to characterize ILC3 progenitors and function at the steady state and during intestinal inflammation. Our second aim is to assess the impact of the cross talk between ILCs and T cells on ILC homeostasis and stromal cell function.

F. Zavala

Infections and inflammation trigger an emergency hematopoiesis aiming at replenishing the immune system with cells that can effectively contribute to immune defense. We hypothesized that the control of potentially deleterious immune responses and of excessive inflammation that may result in chronic immune diseases might be exerted by the emerging hematopoietic progenitor subsets endowed with immunoregulatory properties. We aim to characterize such regulatory progenitors.

P. Paterlini-Brechot

Using immune-cytopathological analyses and high throughput sequencing of single cells, we aim at studying the entire informative potential of circulating cancer cells (CCCs), notably for theranostic purposes, guiding therapeutic choices based on thorough understanding of biological parameters impacting the efficacy of targeted anticancer treatments. A second objective is to develop a reproducible test for as an alternative to amniocentesis and chorionic villous sampling for non-invasive pre-natal diagnosis.

5 main publications

  • Montandon R, Korniotis S, Layseca-Espinosa E, Gras C, Mégret J, Ezine S, Dy M and Zavala F: Innate pro-B cell progenitors protect against type 1 diabetes by regulating autoimmune effector T cells. Proc Natl Acad Sci USA, 2013 110 (24): E2199.
  • Korniotis S, Gras C, Letscher H, Montandon R, Mégret J, Siegert S, Ezine S, Fallon PG, Luther SA, Fillatreau S and Zavala F. Treatment of ongoing autoimmune encephalomyelitis with activated B-cell progenitors maturing into regulatory B cells. Nature Commun 2016.
  • Layseca-Espinosa E, Korniotis S, Montandon R, Gras C, Bouillié M, Gonzalez-Amaro R, Dy M, Zavala F. CCL22-producing CD8α- myeloid dendritic cells mediate regulatory T cell recruitment in response to G-CSF treatment. J Immunol. 2013.
  • Zepponi V, Michaels Lopez V, Martinez-Cingolani C, Boudil A, Pasqualetto V, Skhiri L, Gautreau L, Legrand A, Megret J, Zavala F, Ezine S. Lymphoid Gene Upregulation on Circulating Progenitors Participates in Their T-Lineage Commitment. J Immunol. 2015.
  • Peaudecerf L, Lemos S, Galgano A, Krenn G, Vasseur F, Di Santo JP, Ezine S, Rocha B. Thymocytes may persist and differentiate without any input from bone marrow progenitors. J Exp Med. 2012.
Last 30 publications

2017

  • Gonçalves P, Ferrarini M, Molina-Paris C, Lythe G, Vasseur F, Lim A, Rocha B, Azogui O. A new mechanism shapes the naïve CD8+ T cell repertoire: The selection for full diversity. Mol Immunol. 2017 Feb 14;85:66-80. doi: 10.1016/j.molimm.2017.01.026. [Epub ahead of print]
  • 2016

  • Korniotis S, Gras C, Letscher H, Montandon R, Mégret J, Siegert S, Ezine S, Fallon PG, Luther SA, Fillatreau S, Zavala F. Treatment of ongoing autoimmune encephalomyelitis with activated B-cell progenitors maturing into regulatory B cells. Nat Commun. 2016 Jul 11;7:12134.
  • Zavala F, Korniotis S, Montandon R. Characterization and Immunoregulatory Properties of Innate Pro-B-Cell Progenitors. Methods Mol Biol. 2016;1371:79-88. doi: 10.1007/978-1-4939-3139-2_5.
  • Engert A, Balduini C, Brand A, Coiffier B, Cordonnier C, Döhner H, de Wit TD, Eichinger S, Fibbe W, Green T, de Haas F, Iolascon A, Jaffredo T, Rodeghiero F, Salles G, Schuringa JJ; EHA Roadmap for European Hematology Research. The European Hematology Association Roadmap for European Hematology Research: a consensus document. Haematologica. 2016 Feb;101(2):115-208.
  • Goudin N, Chappert P, Mégret J, Gross DA, Rocha B, Azogui O. Depletion of Regulatory T Cells Induces High Numbers of Dendritic Cells and Unmasks a Subset of Anti-Tumour CD8+CD11c+ PD-1lo Effector T Cells. PLoS One. 2016 Jun 24;11(6):e0157822. doi: 10.1371/journal.pone.0157822.
  • Hamel Y, Mauvais FX, Pham HP, Kratzer R, Marchi C, Barilleau É, Waeckel-Enée E, Arnoux JB, Hartemann A, Cordier C, Mégret J, Rocha B, de Lonlay P, Beltrand J, Six A, Robert JJ, van Endert P. A unique CD8(+) T lymphocyte signature in pediatric type 1 diabetes. J Autoimmun. 2016 Sep;73:54-63.
  • Chaves-Ferreira M, Krenn G, Vasseur F, Barinov A, Gonçalves P, Azogui O, Cumano A, Li Z, Pellegrini S, Rocha B, Laderach D. The cyclin D1 carboxyl regulatory domain controls the division and differentiation of hematopoietic cells. Biol Direct. 2016 Apr 29;11:21.
  • Peaudecerf L, Krenn G, Gonçalves P, Vasseur F, Rocha B. Thymocytes self-renewal: a major hope or a major threat? Immunol Rev. 2016 May;271(1):173-84. doi: 10.1111/imr.12408. Review.
  • Baas M, Besançon A, Goncalves T, Valette F, Yagita H, Sawitzki B, Volk HD, Waeckel-Enée E, Rocha B, Chatenoud L, You S. TGFβ-dependent expression of PD-1 and PD-L1 controls CD8(+) T cell anergy in transplant tolerance. Elife. 2016 Jan 29;5:e08133. doi: 10.7554/eLife.08133.
  • 2015

  • Lopez VM, Ezine S. [Thymic epithelial populations: recently reunified through a unique stem cell]. Med Sci (Paris). 2015 Jun-Jul;31(6-7):591-3.
  • D'Aveni M, Rossignol J, Coman T, Sivakumaran S, Henderson S, Manzo T, Santos e Sousa P, Bruneau J, Fouquet G, Zavala F, Alegria-Prévot O, Garfa-Traoré M, Suarez F, Trebeden-Nègre H, Mohty M, Bennett CL, Chakraverty R, Hermine O, Rubio MT. G-CSF mobilizes CD34+ regulatory monocytes that inhibit graft-versus-host disease. Sci Transl Med. 2015 Apr 1;7(281):281ra42. doi:10.1126/scitranslmed.3010435. PubMed PMID: 25834108.
  • Zepponi V, Michaels Lopez V, Martinez-Cingolani C, Boudil A, Pasqualetto V, Skhiri L, Gautreau L, Legrand A, Megret J, Zavala F, Ezine S. Lymphoid Gene Upregulation on Circulating Progenitors Participates in Their T-Lineage Commitment. J Immunol. 2015 May 29. pii: 1403219. [Epub ahead of print] PubMed PMID: 26026063.
  • 2014

  • Cherrier M. [Innate lymphoid cells: new players of the mucosal immune response]. Med Sci (Paris). 2014 Mar;30(3):280-8.
  • Cording S, Medvedovic J, Cherrier M, Eberl G. Development and regulation of RORγt(+) innate lymphoid cells. FEBS Lett. 2014 Nov 17;588(22):4176-81.
  • Glauzy S, André-Schmutz I, Larghero J, Ezine S, Peffault de Latour R, Moins-Teisserenc H, Servais S, Robin M, Socié G, Clave E, Toubert A. CXCR4-related increase of circulating human lymphoid progenitors after allogeneic hematopoietic stem cell transplantation. PLoS One. 2014 Mar 12;9(3):e91492. doi: 10.1371/journal.pone.0091492. eCollection 2014. PubMed PMID: 24621606; PubMed Central PMCID: PMC3951398.
  • 2013

  • Montandon R, Korniotis S, Layseca-Espinosa E, Gras C, Mégret J, Ezine S, Dy M, Zavala F. Innate pro-B-cell progenitors protect against type 1 diabetes by regulating autoimmune effector T cells. Proc Natl Acad Sci U S A. 2013 Jun 11;110(24):E2199-208.
  • Sung HC, Lemos S, Ribeiro-Santos P, Kozyrytska K, Vasseur F, Legrand A, Charbit A, Rocha B, Evaristo C. Cognate antigen stimulation generates potent CD8(+) inflammatory effector T cells. Front Immunol. 2013 Dec 16;4:452.
  • Boudil A, Skhiri L, Candéias S, Pasqualetto V, Legrand A, Bedora-Faure M, Gautreau-Rolland L, Rocha B, Ezine S. Single-cell analysis of thymocyte differentiation: identification of transcription factor interactions and a major stochastic component in αβ-lineage commitment. PLoS One. 2013 Oct 1;8(10):e73098. doi: 10.1371/journal.pone.0073098. eCollection 2013. PubMed PMID: 24098325; PubMed Central PMCID: PMC3787938.
  • Layseca-Espinosa E, Korniotis S, Montandon R, Gras C, Bouillié M, Gonzalez-Amaro R, Dy M, Zavala F. CCL22-producing CD8α- myeloid dendritic cells mediate regulatory T cell recruitment in response to G-CSF treatment. J Immunol. 2013 Sep 1;191(5):2266-72.
  • 2012

  • Peaudecerf L, Lemos S, Galgano A, Krenn G, Vasseur F, Di Santo JP, Ezine S, Rocha B. Thymocytes may persist and differentiate without any input from bone marrow progenitors. J Exp Med. 2012 Jul 30;209(8):1401-8.
  • Ribeiro-dos-Santos P, Turnbull EL, Monteiro M, Legrand A, Conrod K, Baalwa J, Pellegrino P, Shaw GM, Williams I, Borrow P, Rocha B. Chronic HIV infection affects the expression of the 2 transcription factors required for CD8 T-cell differentiation into cytolytic effectors. Blood. 2012 May 24;119(21):4928-38.
  • Permanent researcher
    Marie Cherrier
    Researcher
    +33 (0)1 72 60 64 96
    Rima El Hage
    Researcher
    +33(0)1 72 60 64 94
    Sophie Ezine
    Researcher
    +33 (0)1 72 60 64 95
    Patrizia Paterlini-Brechot
    Professor Researcher
    +33 (0)1 72 60 64 61
    Benedita Rocha
    Researcher
    +33 (0)1 72 60 64 96
    Flora Zavala
    Researcher
    +33 (0)1 72 60 64 96
    Permanent engineer
    Agnès Legrand
    Assistant in Biological Techniques
    +33 (0)1 72 60 64 93
    Véronique Quellec
    -
    +33 (0)1 72 60 64 93
    Emmanuel Tejerina
    Technician
    +33 (0)1 72 60 64 93
    PhD
    Viviane Agbogan
    PhD Student
    +33(0)1 72 60 64 93
    Priscillia Bresler
    PhD Student
    +33(0)1 72 60 64 98
    Hélène Letscher
    PhD Student
    +33 (0)1 72 60 65 03
    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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