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

TLDR

Regulatory B (Breg) cells are essential for immune homeostasis and have been implicated in autoimmunity models. In a mouse model of antibody‑induced transplantation tolerance, anti‑T cell Ig/mucin domain‑1 and anti‑CD45RB antibody therapy generates antigen‑specific Breg cells that are required for graft survival, can transfer tolerance, expand Treg populations, and promote Foxp3 expression via TGF‑β–dependent mechanisms, with Breg cells also expressing CCR6 and CXCR3.

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.