TGF-β-producing regulatory B cells induce regulatory T cells and promote transplantation tolerance

Eur J Immunol. 2014 Jun;44(6):1728-36. doi: 10.1002/eji.201344062. Epub 2014 May 3.

Abstract

Regulatory B (Breg) cells have been shown to play a critical role in immune homeostasis and in autoimmunity models. We have recently demonstrated that combined anti-T cell immunoglobulin domain and mucin domain-1 and anti-CD45RB antibody treatment results in tolerance to full MHC-mismatched islet allografts in mice by generating Breg cells that are necessary for tolerance. Breg cells are antigen-specific and are capable of transferring tolerance to untreated, transplanted animals. Here, we demonstrate that adoptively transferred Breg cells require the presence of regulatory T (Treg) cells to establish tolerance, and that adoptive transfer of Breg cells increases the number of Treg cells. Interaction with Breg cells in vivo induces significantly more Foxp3 expression in CD4(+) CD25(-) T cells than with naive B cells. We also show that Breg cells express the TGF-β associated latency-associated peptide and that Breg-cell mediated graft prolongation post-adoptive transfer is abrogated by neutralization of TGF-β activity. Breg cells, like Treg cells, demonstrate preferential expression of both C-C chemokine receptor 6 and CXCR3. Collectively, these findings suggest that in this model of antibody-induced transplantation tolerance, Breg cells promote graft survival by promoting Treg-cell development, possibly via TGF-β production.

Keywords: Breg cells; TGF-β; Tolerance; Transplant; Treg cells.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adoptive Transfer
  • Allografts
  • Animals
  • B-Lymphocyte Subsets / immunology*
  • B-Lymphocyte Subsets / pathology
  • Forkhead Transcription Factors / genetics
  • Forkhead Transcription Factors / immunology
  • Gene Expression Regulation / genetics
  • Gene Expression Regulation / immunology
  • Graft Survival / genetics
  • Graft Survival / immunology*
  • Islets of Langerhans Transplantation / immunology*
  • Mice
  • Mice, Inbred BALB C
  • Mice, Knockout
  • Receptors, CCR6 / genetics
  • Receptors, CCR6 / immunology
  • Receptors, CXCR3 / genetics
  • Receptors, CXCR3 / immunology
  • T-Lymphocytes, Regulatory / immunology*
  • T-Lymphocytes, Regulatory / pathology
  • Transforming Growth Factor beta / genetics
  • Transforming Growth Factor beta / immunology*
  • Transplantation Tolerance*

Substances

  • CCR6 protein, mouse
  • Cxcr3 protein, mouse
  • Forkhead Transcription Factors
  • Foxp3 protein, mouse
  • Receptors, CCR6
  • Receptors, CXCR3
  • Transforming Growth Factor beta