Abstract

Previous studies aimed at identifying biomarkers of tolerance in kidney transplant patients have revealed an expansion of peripheral blood B cells and over- expression of B cell-related genes. In humans, Memory, Naïve and Transitional B cells are the main B cell subsets found in circulation, and it is has been shown that the Transitional subset, defined by its regulatory properties, is expanded in tolerant recipients compared to non-tolerant kidney transplant patients. However, the role this population plays in kidney transplantation tolerance remains unclear. Here, we report three different mechanisms to explain the contribution of B cells in transplantation tolerance. Kidney transplant patients were divided into five groups; tolerant, stable, monotherapy, patients who lost tolerance and chronic rejector. In addition, this study also included a group of age/gender-matched healthy volunteers. B cells from each group of patients were tested for antigen presentation, antibody production, cytokine production, and co-stimulatory function. B cells from tolerant patients produced higher levels of IL-10 and lower levels of TNF-α than B cells from chronic rejector after CD40 and CpG activation. Moreover, B lymphocytes from tolerant patients also exhibited a failure in the BCR signalling pathway, suggesting a certain degree of anergy or responsiveness by these cells. Donor- specific assays revealed that B cells from tolerant patients were inefficient to recognise donor-antigens, compared to B cells from chronic rejector. This impairment prevented the triggering of the Th1 response by recipient CD4+ T cells and donor-specific antibody production by Plasma cells. Finally, Transitional B cells were the lowest CD4+ T cell- activating cells, compared to Naïve and Memory B cells. This reduced CD4+ T cell activation was due to low cell viability, reduced CD86 expression and high IL-10 production. In conclusion, these data suggest that B cells from kidney tolerant recipients contributed to maintaining organ acceptance and graft survival by donor-specific and non-specific regulatory properties exhibited by all their subsets, especially Transitional B cells.