Regulatory B Cells with a Partial Defect in CD40 Signaling and Overexpressing Granzyme B Transfer Allograft Tolerance in Rodents

Abstract

Emerging knowledge regarding B cells in organ transplantation has demonstrated that these cells can no longer be taken as mere generators of deleterious Abs but can also act as beneficial players. We previously demonstrated in a rat model of cardiac allograft tolerance induced by short-term immunosuppression an accumulation in the blood of B cells overexpressing inhibitory molecules, a phenotype also observed in the blood of patients that spontaneously develop graft tolerance. In this study, we demonstrated the presence in the spleen of regulatory B cells enriched in the CD24intCD38+CD27+IgD−IgM+/low subpopulation, which are able to transfer donor-specific tolerance via IL-10 and TGF-β1–dependent mechanisms and to suppress in vitro TNF-α secretion. Following anti-CD40 stimulation, IgD−IgM+/low B cells were blocked in their plasma cell differentiation pathway, maintained high expression of the inhibitory molecules CD23 and Bank1, and upregulated Granzyme B and Irf4, two molecules described as highly expressed by regulatory B cells. Interestingly, these B cells recognized specifically a dominant donor Ag, suggesting restricted specificity that could lead to a particular B cell response. Regulatory B cells were not required for induction of tolerance and appeared following Foxp3+CD4+CD25+ regulatory T cells, suggesting cooperation with regulatory T cells for their expansion. Nevertheless, following transfer to new recipients, these B cells migrated to the allograft, kept their regulatory profile, and promoted local accumulation of Foxp3+CD4+CD25+ regulatory T cells. Mechanisms of regulatory B cells and their cell therapy potential are important to decipher in experimental models to pave the way for future developments in the clinic.

B Cell Receptor Genes Associated With Tolerance Identify a Cohort of Immunosuppressed Patients With Improved Renal Allograft Graft Function

“…Along this line, it is also interesting to note that immature B cells have been shown to be relatively ineffective in promoting T cell responses in murine models (25). This hypothesis, though unproven, is consistent with recent reports in experimental transplant models that tolerance is associated with increased numbers of B cells with regulatory properties that are capable of transferring tolerance as well as data from tolerant human kidney transplant recipients demonstrating that a population of B cells capable of suppressing CD4 effector cells in vitro (12, 24). Even absent the formal demonstration that changes in B cells and B cell-associated genes identify tolerant renal transplant recipients, the identification of B cell-related markers that identify a cohort with improved function could have important prognostic and mechanistic implications.…”

Dynamics of B Cell Recovery In Kidney/Bone Marrow Transplant Recipients

“…A consensus emerged around transitional B cells, a population of presumably immature cells, as it was shown that this B cell subset was increased in tolerant subjects in several independent studies 2,4,5,8 . Other B cell subsets were also identified as elevated in tolerant subjects, including memory B cells and granzyme B+ cells with a plasma cell phenotype 1,3,6 .…”

Tracing Donor-MHC Class II Reactive B cells in Mouse Cardiac Transplantation

“…In those studies, IL-10 produced by B cells have been shown to play a critical role, but the phenotype and the antigen-specificity of the IL-10 producing B cells, and the micro-anatomical location of these IL-10-producing Bregs that allow them to modulate T cell responses, require further clarification. Additionally observations that operationally tolerant kidney transplant recipients have enriched subsets of B cells compared to stable recipients on immunosuppression have lead some investigators to hypothesize a role for B cells, and potentially regulatory B cells, in clinical transplant tolerance 18–24 . Collectively these findings have intensified interest in understanding the fate of alloreactive B cells in rejection and tolerance.…”