title: Human regulatory B cells control the TFHcell response.
abstract: BACKGROUND
  Follicular helper T (TFH) cells support terminal B-cell differentiation. Human regulatory B (Breg) cells modulate cellular responses, but their control of TFHcell-dependent humoral immune responses is unknown.
  
  
  OBJECTIVE
  We sought to assess the role of Breg cells on TFHcell development and function.
  
  
  METHODS
  Human T cells were polyclonally stimulated in the presence of IL-12 and IL-21 to generate TFHcells. They were cocultured with B cells to induce their terminal differentiation. Breg cells were included in these cultures, and their effects were evaluated by using flow cytometry and ELISA.
  
  
  RESULTS
  B-cell lymphoma 6, IL-21, inducible costimulator, CXCR5, and programmed cell death protein 1 (PD-1) expressions increased on stimulated human T cells, characterizing TFHcell maturation. In cocultures they differentiated B cells into CD138+plasma and IgD-CD27+memory cells and triggered immunoglobulin secretions. Breg cells obtained by Toll-like receptor 9 and CD40 activation of B cells prevented TFHcell development. Added to TFHcell and B-cell cocultures, they inhibited B-cell differentiation, impeded immunoglobulin secretions, and expanded Foxp3+CXCR5+PD-1+follicular regulatory T cells. Breg cells modulated IL-21 receptor expressions on TFHcells and B cells, and their suppressive activities involved CD40, CD80, CD86, and intercellular adhesion molecule interactions and required production of IL-10 and TGF-β.
  
  
  CONCLUSIONS
  Human Breg cells control TFHcell maturation, expand follicular regulatory T cells, and inhibit the TFHcell-mediated antibody secretion. These novel observations demonstrate a role for the Breg cell in germinal center reactions and suggest that deficient activities might impair the TFHcell-dependent control of humoral immunity and might lead to the development of aberrant autoimmune responses.
authors.affiliation: Université de Brest, INSERM U1227, Lymphocytes B et Autoimmunité, and LabEx IGO, Brest, France.
authors.forename: Achouak
authors.initials: A
authors.lastname: Achour
authors.affiliation: Université de Brest, INSERM U1227, Lymphocytes B et Autoimmunité, and LabEx IGO, Brest, France.
authors.forename: Quentin
authors.initials: Q
authors.lastname: Simon
authors.affiliation: Université de Brest, INSERM U1227, Lymphocytes B et Autoimmunité, and LabEx IGO, Brest, France.
authors.forename: Audrey
authors.initials: A
authors.lastname: Mohr
authors.affiliation: Université de Brest, INSERM U1227, Lymphocytes B et Autoimmunité, and LabEx IGO, Brest, France; CHRU Morvan, Laboratoire d'Immunologie, Brest, France.
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Séité
authors.affiliation: Université de Brest, INSERM U1227, Lymphocytes B et Autoimmunité, and LabEx IGO, Brest, France; CHRU Morvan, Laboratoire d'Immunologie, Brest, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Youinou
authors.affiliation: CHRU Morvan, Laboratoire d'Immunologie, Brest, France.
authors.forename: Boutahar
authors.initials: B
authors.lastname: Bendaoud
authors.affiliation: Faculty of Pharmacy, Department of Immunology, Research Unit (03/UR/07-02), Monastir, Tunisia.
authors.forename: Ibtissem
authors.initials: I
authors.lastname: Ghedira
authors.affiliation: Université de Brest, INSERM U1227, Lymphocytes B et Autoimmunité, and LabEx IGO, Brest, France; CHRU Morvan, Laboratoire d'Immunologie, Brest, France.
authors.forename: Jacques-Olivier
authors.initials: JO
authors.lastname: Pers
authors.affiliation: Université de Brest, INSERM U1227, Lymphocytes B et Autoimmunité, and LabEx IGO, Brest, France; CHRU Morvan, Laboratoire d'Immunologie, Brest, France. Electronic address: christophe.jamin@univ-brest.fr.
authors.forename: Christophe
authors.initials: C
authors.lastname: Jamin
mesh_terms: D060151:B-Lymphocytes, Regulatory / Q000276:immunology* / Q000502:physiology; D002454:Cell Differentiation; D002478:Cells, Cultured; D018920:Coculture Techniques; D006801:Humans; D018664:Interleukin-12 / Q000276:immunology; D007378:Interleukins / Q000276:immunology; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology* / Q000502:physiology; D000098546:Interleukin-21
chemical_list: D007378:Interleukins; D018664:Interleukin-12; D000098546:Interleukin-21
keywords: IL-12; IL-21; Regulatory B cells; antibody production; follicular T helper cells; humoral immune response