title: B-Cells induce regulatory T cells through TGF-β/IDO production in A CTLA-4 dependent manner.
abstract: A number of studies have suggested that B cell mediated-regulation contributes to the establishment of immunological tolerance. However, the precise mechanisms by which regulatory B cells establish and maintain tolerance in humans remain to be determined. The objective of the current study is to understand the cellular and molecular bases of B-cell regulatory functions in humans. To describe the mechanisms regulating the functional plasticity of regulatory B cells, we used an in vitro co-culture model based on autologous mixed lymphocyte cultures involving freshly isolated B and T cells. The results show that activated B cells regulate T cell proliferation through producing transforming growth factor (TGF)-β and indoleamine 2,3-dioxygenase (IDO). The production of TGF-β and IDO leads to the induction of not only "natural" regulatory T cells but also of TGF-β-producing CD4(+) T cells and IL-10-producing regulatory T cells. Furthermore, we evidenced for the first time that CTLA-4 induces B-cells to produce IDO and to become effective induced regulatory B cells (iBregs). This study emphasizes a novel regulatory axis and open news insights in how to manage regulatory B cell functions in autoimmunity.
authors.affiliation: EA2216, INSERM ESPRI, ERI 29, Université de Brest and LabEx IGO, Brest, France.
authors.forename: A
authors.initials: A
authors.lastname: Nouël
authors.affiliation: EA2216, INSERM ESPRI, ERI 29, Université de Brest and LabEx IGO, Brest, France.
authors.forename: P
authors.initials: P
authors.lastname: Pochard
authors.affiliation: EA2216, INSERM ESPRI, ERI 29, Université de Brest and LabEx IGO, Brest, France.
authors.forename: Q
authors.initials: Q
authors.lastname: Simon
authors.affiliation: EA2216, INSERM ESPRI, ERI 29, Université de Brest and LabEx IGO, Brest, France; Department of Nephrology, CHRU Cavale Blanche, Brest, France.
authors.forename: I
authors.initials: I
authors.lastname: Ségalen
authors.affiliation: EA2216, INSERM ESPRI, ERI 29, Université de Brest and LabEx IGO, Brest, France; Department of Nephrology, CHRU Cavale Blanche, Brest, France.
authors.forename: Y
authors.initials: Y
authors.lastname: Le Meur
authors.affiliation: EA2216, INSERM ESPRI, ERI 29, Université de Brest and LabEx IGO, Brest, France. Electronic address: pers@univ-brest.fr.
authors.forename: J O
authors.initials: JO
authors.lastname: Pers
authors.affiliation: EA2216, INSERM ESPRI, ERI 29, Université de Brest and LabEx IGO, Brest, France.
authors.forename: S
authors.initials: S
authors.lastname: Hillion
mesh_terms: D015551:Autoimmunity; D060151:B-Lymphocytes, Regulatory / Q000276:immunology*; D060908:CTLA-4 Antigen / Q000378:metabolism*; D049109:Cell Proliferation; D002478:Cells, Cultured; D018920:Coculture Techniques; D006801:Humans; D007108:Immune Tolerance; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000378:metabolism*; D016753:Interleukin-10 / Q000378:metabolism; D007959:Lymphocyte Culture Test, Mixed; D016131:Lymphocyte Subsets / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D016212:Transforming Growth Factor beta / Q000378:metabolism*
chemical_list: D060908:CTLA-4 Antigen; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D016212:Transforming Growth Factor beta; D016753:Interleukin-10
keywords: CTLA-4; Indoleamine 2.3-dioxygenase; Regulatory B cells; TGF-beta