title: Transitional-2 B cells acquire regulatory function during tolerance induction and contribute to allograft survival.
abstract: In humans, tolerance to renal transplants has been associated with alterations in B-cell gene transcription and maintenance of the numbers of circulating transitional B cells. Here, we use a mouse model of transplantation tolerance to investigate the contribution of B cells to allograft survival. We demonstrate that transfer of B cells from mice rendered tolerant to MHC class I mismatched skin grafts can prolong graft survival in a dose-dependent and antigen-specific manner to a degree similar to that afforded by graft-specific regulatory T (Treg) cells. Tolerance in this model was associated with an increase in transitional-2 (T2) B cells. Only T2 B cells from tolerized mice, not naïve T2 nor alloantigen experienced T2, were capable of prolonging skin allograft survival, and suppressing T-cell activation. Tolerized T2 B cells expressed lower levels of CD86, increased TIM-1, and demonstrated a preferential survival in vivo. Furthermore, we demonstrate a synergistic effect between tolerized B cells and graft-specific Treg cells. IL-10 production by T2 B cells did not contribute to tolerance, as shown by transfer of B cells from IL-10(-/-) mice. These results suggest that T2 B cells in tolerant patients may include a population of regulatory B cells that directly inhibit graft rejection.
authors.affiliation: MRC Centre for Transplantation, King's College London Guy's Hospital, London, UK.
authors.forename: Aurélie
authors.initials: A
authors.lastname: Moreau
authors.forename: Paul A
authors.initials: PA
authors.lastname: Blair
authors.forename: Jian-Guo
authors.initials: JG
authors.lastname: Chai
authors.forename: Kulachelvy
authors.initials: K
authors.lastname: Ratnasothy
authors.forename: Emilie
authors.initials: E
authors.lastname: Stolarczyk
authors.forename: Rowa
authors.initials: R
authors.lastname: Alhabbab
authors.forename: Chloe L
authors.initials: CL
authors.lastname: Rackham
authors.forename: Peter M
authors.initials: PM
authors.lastname: Jones
authors.forename: Lesley
authors.initials: L
authors.lastname: Smyth
authors.forename: Raul
authors.initials: R
authors.lastname: Elgueta
authors.forename: Jane K
authors.initials: JK
authors.lastname: Howard
authors.forename: Robert I
authors.initials: RI
authors.lastname: Lechler
authors.forename: Giovanna
authors.initials: G
authors.lastname: Lombardi
mesh_terms: D064591:Allografts; D000818:Animals; D006085:Graft Survival / Q000235:genetics / Q000276:immunology*; D016753:Interleukin-10 / Q000235:genetics / Q000276:immunology; D008213:Lymphocyte Activation; D051379:Mice; D018345:Mice, Knockout; D054448:Precursor Cells, B-Lymphoid / Q000276:immunology*; D016038:Skin Transplantation; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D023001:Transplantation Tolerance
chemical_list: C556062:IL10 protein, mouse; D016753:Interleukin-10
keywords: Regulatory B cells; Regulatory T cells; T2 B cells; Tolerance; Transplantation