Tolerant Kidney Transplant Patients Produce B Cells with Regulatory Properties

Abstract

Whereas a B cell-transcriptional profile has been recorded for operationally tolerant kidney graft patients, the role that B cells have in this tolerance has not been reported. In this study, we analyzed the role of B cells from operationally tolerant patients, healthy volunteers, and kidney transplant recipients with stable graft function on T cell suppression. Proliferation, apoptosis, and type I proinflammatory cytokine production by effector CD4 + CD25 2 T cells were measured after anti-CD3/anti-CD28 stimulation with or without autologous B cells. We report that B cells inhibit CD4 + CD25 2 effector T cell response in a dosedependent manner. This effect required B cells to interact with T-cell targets and was achieved through a granzyme B (GzmB)-dependent pathway. Tolerant recipients harbored a higher number of B cells expressing GzmB and displaying a plasma cell phenotype. Finally, GzmB + B-cell number was dependent on IL-21 production, and B cells from tolerant recipients but not from other patients positively regulated both the number of IL-21 + T cells and IL-21 production, suggesting a feedback loop in tolerant recipients that increases excessive B cell activation and allows regulation to take place. These data provide insights into the characterization of B cell-mediated immunoregulation in clinical tolerance and show a potential regulatory effect of B cells on effector T cells in blood from patients with operationally tolerant kidney grafts.

CD4+ T Cell–Derived IL-21 and Deprivation of CD40 Signaling Favor the In Vivo Development of Granzyme B–Expressing Regulatory B Cells in HIV Patients

“…Nevertheless, they suggest the possibility that the absence of the NEMO-dependent component of CD40/CD40L signaling allows high percentages of GraB cells to develop in vivo after IL-21-mediated activation, such as during acute infections, whereas its presence may normally suppress GraB cell induction. Of note, our hypothesis is further substantiated by independent studies demonstrating that operationally tolerant kidney graft patients display a significantly enhanced number of GrB + B cells with regulatory potential (45). These B cells also potently suppress effector T cell proliferation in a GrB-dependent, yet IL-10-independent, manner and exhibit a partial block of their CD40 signaling status, strongly suggesting that these cells are identical to the GraB cells described in this study (personal communication, Drs.…”

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

“…Therefore, in our model, the regulatory B cells when they reencountered the alloantigens in the spleen and because of their defect in CD40 signaling may lead to the generation of granzyme B + plasmablast-like regulatory B cells that accumulated particularly in the graft tissue. Interestingly, a higher number of granzyme B + regulatory B cells exhibiting a plasmablast-like phenotype are also reported in blood from patients with operationally tolerant kidney grafts (52). Recently, the differentiation of plasmablast regulatory B cells has been shown, specifically in the draining lymph nodes during experimental autoimmune encephalomyelitis.…”

B Cells, Antibodies, and More

“…Several independent reports provided evidence that operationally tolerant kidney transplant recipients (those who have stable graft function in the absence of all pharmacologic immunosuppression) exhibit various B-cell alterations within their peripheral blood mononuclear cells, including increased B-cell numbers, B cell-specific gene expression, transitional B cells producing IL-10, memory B cells with an inhibitory phenotype, and granzyme B-expressing B cells that curtail proliferation and cause apoptosis of CD4 effector T cells (138)(139)(140)(141)(142). These studies provide the impetus to explore new strategies to induce or enhance regulatory B cells in humans for the purpose of achieving tolerance or minimizing long-term, conventional immunosuppression after kidney transplantation.…”