Regulatory B cells require antigen recognition for effective allograft tolerance induction

Abstract

Through multiple mechanisms, regulatory B cells (Breg) have been shown to play an important role in the development of allograft tolerance. However, a careful understanding of the role of antigen‐specificity in Breg‐mediated allograft tolerance has remained elusive. In experimental models of islet and cardiac transplantation, it has been established that Bregs can be induced in vivo by anti‐CD45RB ± anti‐TIM1antibody treatment, resulting in prolonged, Breg‐dependent allograft tolerance. The importance of Breg antigen recognition has been suggested but not confirmed through adoptive transfer experiments, using tolerant WT C57BL/6 animals challenged with either BALB/c or C3H grafts. However, the importance of receptor‐specificity has not been formally tested. Here, we utilize the novel ovalbumin‐specific B cell receptor transnuclear (OBI) mice in multiple primary tolerance and adoptive transfer experiments to establish that Breg‐dependent allograft tolerance relies on antigen recognition by B cells. Additionally, we identify that this Breg‐dependent tolerance relies on the function of transforming growth factor‐β. Together, these experiments mark important progress toward understanding how best to improve Breg‐mediated allograft tolerance.

Immune Equilibrium Depends on the Interaction Between Recognition and Presentation Landscapes

“…However, in this case, a transition Beff ↔ Breg could be primarily associated with the peculiarities of the microenvironment and only indirectly mediated by the shifts of spectra of the presented antigens and the conditions of their presentations via T cells (91,(102)(103)(104). Still, in some cases, the induction and functional activity of Bregs depend on the recognition of cognate antigens by Breg cells; and the suppression activity of Bregs can be mediated by direct B-T cellular interaction, which confirms the possibility of the Ag-specific effect of Bregs (105,106). Thus, the conditions of the microenvironment and spectra of B-dependent antigens in the microenvironment of B cells influence their functional specialization; and an irrelevant transdifferentiation Beff ↔ Breg can underlie the pathogenesis of different pathologies.…”

TGF‐β‐secreting regulatory B cells: unsung players in immune regulation

“…These experiments in mice demonstrate that Breg-dependent tolerance relies on the function of TGF-b and that this process is, at least in some circumstances, antigen-specific. 71 In NHP studies and human clinical transplants, there is mounting evidence that Bregs play a key role in transplant outcome. 72 In an interesting clinical trial for kidney transplants using B-cell depletion as the only induction therapy, there appeared to be an increased incidence of early rejection, possibly because of the elimination of the Breg subset 73 .…”

Regulatory B cells in transplantation: roadmaps to clinic

“…BCR signalling pathways may drive the capacity of B cells to express IL‐10, thereby selecting for antigen‐specific Breg in vivo . The requirement for Breg antigen specificity in transplantation was indicated when the adoptive transfer of mouse TIM‐1 + Bregs from tolerant recipients of H2 d islet allografts prolonged survival of H2 d grafts but not those of 3 rd party H2 k grafts [3,51]. In a series of elegant experiments, tolerized C57BL/6 mice with ovalbumin (OVA)‐specific BCR were used to demonstrate tolerance in the presence of OVA + skin grafts, but not when the allograft lacked a recognizable antigen (BM12 skin grafts from MHC class II variant C57BL/6 mice).…”