title: IL-10 from marginal zone precursor B cells controls the differentiation of Th17, Tfh and Tfr cells in transplantation tolerance.
abstract: B cells are known to control CD4T cell differentiation in secondary lymphoid tissues. We hypothesized that IL-10 expression by marginal zone precursor (MZP) regulatory B cells controls the differentiation and positioning of effector and regulatory T cells during tolerization. Costimulatory blockade with donor-specific transfusion (DST) and anti-CD40L mAb in C57BL/6 mice induced tolerance to allogeneic cardiac allograft. B cell depletion or IL-10 deficiency in B cells prevented tolerance, resulting in decreased follicular regulatory CD4(+) T cells (Tfr) and increased IL-21 expression by T follicular helper (Tfh) cells in the B cell and T cell zones. IL-21 acted with IL-6 to induce CCR6(+) Th17 that caused rejection. Deficiency or blockade of IL-6, IL-21, IL-21R, or CCR6 prevented B cell depletion-induced acute cellular rejection; while agonistic mCCL20-Ig induced rejection. Adoptive transfer of IL-10(+/+) MZP in tolerogen treated CD19-Cre(+/-):IL-10(fl/fl) mice rescued the localization of Tfh and Tfr cells in the B cell follicle and prevented allograft rejection. MZP B cell IL-10 is necessary for tolerance and controls the differentiation and position of Th17, Tfh and Tfr cells in secondary lymphoid tissues. This has implications for understanding tolerance induction and how B cell depletion may prevent tolerance.
authors.affiliation: National Centre for Cell Science, Pune, MH, India. Electronic address: glal@nccs.res.in.
authors.forename: Girdhari
authors.initials: G
authors.lastname: Lal
authors.affiliation: National Centre for Cell Science, Pune, MH, India.
authors.forename: Neeraja
authors.initials: N
authors.lastname: Kulkarni
authors.affiliation: Departments of Surgery and Microbiology and Immunology, and Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine, Baltimore, MD 21201, United States.
authors.forename: Yumi
authors.initials: Y
authors.lastname: Nakayama
authors.affiliation: National Centre for Cell Science, Pune, MH, India.
authors.forename: Amit K
authors.initials: AK
authors.lastname: Singh
authors.affiliation: National Centre for Cell Science, Pune, MH, India.
authors.forename: Apoorva
authors.initials: A
authors.lastname: Sethi
authors.affiliation: Departments of Surgery and Microbiology and Immunology, and Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine, Baltimore, MD 21201, United States.
authors.forename: Bryna E
authors.initials: BE
authors.lastname: Burrell
authors.affiliation: Departments of Surgery and Microbiology and Immunology, and Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine, Baltimore, MD 21201, United States.
authors.forename: C Colin
authors.initials: CC
authors.lastname: Brinkman
authors.affiliation: Departments of Surgery and Microbiology and Immunology, and Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine, Baltimore, MD 21201, United States.
authors.forename: Daiki
authors.initials: D
authors.lastname: Iwami
authors.affiliation: Departments of Surgery and Microbiology and Immunology, and Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine, Baltimore, MD 21201, United States.
authors.forename: Tianshu
authors.initials: T
authors.lastname: Zhang
authors.affiliation: Institute for Immunology, University of Regensburg, Regensburg, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Hehlgans
authors.affiliation: Departments of Surgery and Microbiology and Immunology, and Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine, Baltimore, MD 21201, United States. Electronic address: JBromberg@smail.umaryland.edu.
authors.forename: Jonathan S
authors.initials: JS
authors.lastname: Bromberg
mesh_terms: D019264:Adoptive Transfer; D064591:Allografts; D000818:Animals; D015415:Biomarkers; D002454:Cell Differentiation; D018858:Germinal Center / Q000276:immunology* / Q000378:metabolism; D006084:Graft Rejection / Q000276:immunology; D016130:Immunophenotyping; D016753:Interleukin-10 / Q000172:deficiency / Q000378:metabolism*; D008212:Lymphocyte Depletion; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010641:Phenotype; D054448:Precursor Cells, B-Lymphoid / Q000276:immunology* / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D006377:T-Lymphocytes, Helper-Inducer / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D058504:Th17 Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D023001:Transplantation Tolerance
chemical_list: D015415:Biomarkers; D016753:Interleukin-10
keywords: B cells; Breg; Costimulatory blockade; Tfh; Th17; Transplantation tolerance