Whereas a B cell transcriptional profile has been recorded for operationally tolerant kidney graft patients, the role that B cells may play in this process of tolerance has not been reported yet. We analyzed the role of B cells from operationally tolerant patients (n=12), healthy volunteers (n=17) and kidney-transplant recipients with stable graft function (n=17) on T cell response. We looked at proliferation, apoptosis and type I pro-inflammatory cytokine production by effector CD4+CD25- T cells after anti-CD3/anti-CD28 stimulation with or without autologous B cells. We report that B cells from tolerant recipients are able to inhibit CD4+CD25- effector T cell response in a dose dependent manner. We showed that this effect needs Breg cells to interact with their T cell targets, is independent from IL-10, IFN-γ and TGF-β but acts through a GzmB dependent pathway. Tolerant recipients harbor a higher number of these B cells expressing GzmB and displaying a CD27, CD38, CD138 plasma cell-phenotype. Finally, B cells from tolerant recipients regulate the number of IL-21+ T cells and IL-21 production and GzmB+ Breg cells are abolished by IL-21 blockade, suggesting a negative feedback loop in these patients, allowing regulation to take place. These data provide novel insights into the characterization of B cell–mediated immunoregulation in tolerance in human and show for the first time a regulatory role for B cells with a specific plasma cell phenotype on effector T cells in blood from patients with operational tolerance.

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