title: Interleukin-10 From Marginal Zone Precursor B-Cell Subset Is Required for Costimulatory Blockade-Induced Transplantation Tolerance.
abstract: BACKGROUND
  Blocking CD40-CD40L costimulatory signals induces transplantation tolerance. Although B-cell depletion prevents alloantibody formation, nonhumoral functions of B cells in tolerance have not been well characterized. We investigated whether specific subsets of B cell or B cell-derived interleukin (IL)-10 contribute to tolerance.
  
  
  METHODS
  Wild type C57BL/6, or B cell-specific interleukin (IL)-10 (CD19-Cre::IL-10) mice, received vascularized BALB/c cardiac allografts. BALB/c donor-specific splenocyte transfusion and anti-CD40L monoclonal antibody were used as tolerogen. B cells were depleted with antimouse CD20 monoclonal antibody. Various B-cell subsets were purified and characterized by flow cytometry, reverse transcription polymerase chain reaction, and adoptive transfer.
  
  
  RESULTS
  B-cell depletion prevented costimulatory blockade-induced allogeneic tolerance. Costimulatory blockade increased IL-10 in marginal zone precursor (MZP) B cells, but not other subsets. In particular, costimulatory blockade did not change other previously defined regulatory B-cell subsets (Breg), including CD5CD1d Breg or expression of TIM1 or TIM4 on these Breg or other Breg cell subsets. Costimulatory blockade also induced IL-21R expression in MZP B cells, and IL-21R MZP B cells expressed even more IL-10. B-cell depletion or IL-10 deficiency in B cells prevented tolerance in a cardiac allograft model, resulting in rapid acute cardiac allograft rejection. Adoptive transfer of wild type MZP B cells but not other subsets to B cell-specific IL-10 deficient mice prevented graft rejection.
  
  
  CONCLUSIONS
  CD40 costimulatory blockade induces MZP B cell IL-10 which is necessary for tolerance. These observations have implications for understanding tolerance induction and how B cell depletion may prevent tolerance.
authors.affiliation: 1 National Centre for Cell Science, Pune, MH, India. 2 Departments of Surgery and Microbiology and Immunology, and Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine, Baltimore, MD.
authors.forename: Girdhari
authors.initials: G
authors.lastname: Lal
authors.forename: Yumi
authors.initials: Y
authors.lastname: Nakayama
authors.forename: Apoorva
authors.initials: A
authors.lastname: Sethi
authors.forename: Amit K
authors.initials: AK
authors.lastname: Singh
authors.forename: Bryna E
authors.initials: BE
authors.lastname: Burrell
authors.forename: Neeraja
authors.initials: N
authors.lastname: Kulkarni
authors.forename: C Colin
authors.initials: CC
authors.lastname: Brinkman
authors.forename: Daiki
authors.initials: D
authors.lastname: Iwami
authors.forename: Tianshu
authors.initials: T
authors.lastname: Zhang
authors.forename: Jonathan S
authors.initials: JS
authors.lastname: Bromberg
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D019013:CD40 Antigens / Q000276:immunology / Q000378:metabolism; D023201:CD40 Ligand / Q000276:immunology / Q000378:metabolism; D002478:Cells, Cultured; D006084:Graft Rejection / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D006085:Graft Survival; D016027:Heart Transplantation / Q000009:adverse effects; D006801:Humans; D016753:Interleukin-10 / Q000172:deficiency / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D053738:Interleukin-21 Receptor alpha Subunit / Q000276:immunology / Q000378:metabolism; D008212:Lymphocyte Depletion; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009206:Myocardium / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D010641:Phenotype; D054448:Precursor Cells, B-Lymphoid / Q000276:immunology / Q000378:metabolism* / Q000637:transplantation; D015398:Signal Transduction; D013997:Time Factors; D023001:Transplantation Tolerance
chemical_list: D000911:Antibodies, Monoclonal; D019013:CD40 Antigens; C556062:IL10 protein, mouse; C508118:Il21r protein, mouse; D053738:Interleukin-21 Receptor alpha Subunit; D016753:Interleukin-10; D023201:CD40 Ligand
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