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

Abstract

Summary Regulatory B cells (Bregs) have been shown to play a critical role in immune homeostasis and in autoimmunity models. We have recently demonstrated that combined anti-TIM-1 and anti-CD45RB antibody treatment results in tolerance to full MHC-mismatched islet allografts in mice by generating Bregs that are necessary for tolerance. Bregs are antigen-specific and are capable of transferring tolerance to untreated, transplanted animals. Here we demonstrate that adoptively transferred Bregs require the presence of Tregs to establish tolerance, and that adoptive transfer of Bregs increases the number of Tregs. Interaction with Bregs in vivo induces significantly more Foxp3 expression in CD4+CD25− T cells than with naive B cells. We also show that Bregs express the TGF-β associated latency-associated peptide (LAP) and that Breg-mediated graft prolongation post-adoptive transfer is abrogated by neutralization of TGF-β activity. Regulatory B cells, like regulatory T cells, demonstrate preferential expression of both CCR6 and CXCR3. Collectively, these findings suggest that in this model of antibody-induced transplantation tolerance, Bregs promote graft survival by promoting Treg development, possibly via TGF-β production.

Compensatory Regulatory Networks between CD8 T, B, and Myeloid Cells in Organ Transplantation Tolerance

“…The use of regulatory cells as a therapeutic in transplantation is one of the current major challenge and aims at developing more specific and efficient targeted strategies (1,35,36). A better understanding of such pathways could provide basis for combined cellular immunotherapies (5). Our studies also provide a beware signal on emergence of less efficient regulatory populations.…”

“…Despite the fact that we could not specifically deplete CD4 + Tregs in absence of specific tools in rats, we believe that they play an important role in supporting the function of Bregs and RegMCs. Although Bregs and RegMCs have already been described as involved in transplantation tolerance (3,5,11,12,39), their possible synergistic and equal involvement in inhibition of antidonor immune responses had never been described. As for CD8 + CD45RC low Tregs, we believe that Bregs and RegMCs emerge at early time point in presence of Ags (14).…”

“…In particular, the regulatory potential of new subsets such as B cells or myeloid cells (MCs) has been unraveled and lots of efforts are being done to identify specific markers and mechanisms, as it has been done for CD4 + regulatory T cells (Tregs), and more recently for CD8 + Tregs (1). We and others have demonstrated the immunoregulatory potential of regulatory B cells (Bregs) in transplantation tolerance in rodents and human (2)(3)(4)(5)(6)(7)(8) and described different subsets of Bregs with distinct mechanisms (9,10). Regulatory MCs (RegMCs) have been less studied, but data are emerging demonstrating their protective potential in rodent models of transplantation, but also more recently in clinical trials (11,12).…”

THERAPY OF ENDOCRINE DISEASE: Islet transplantation for type 1 diabetes: so close and yet so far away

“…The chemokine CCL22 can be used to recruit the endogenous T regs toward islets in order to prevent an immune attack against them (163). Regulatory B cells can induce T regs and contribute to tolerance induction against pancreatic islets by secretion of TGF-b (164). Attenuation of donor reactive T cells increases the efficacy of T regs therapy in prevention of islet allograft rejection (165).…”

Bregs in Chronic HBV: Is It Time for Bragging Rights?

“…While Bregs are usually recognized as CD19?IL-10?, Breg secreting TGF-b have also been described [12].…”