Marginal zone B cells are required for optimal humoral responses to allograft

Antibody-mediated rejection (AMR) is among the leading causes of graft failure in solid organ transplantation. However, AMR treatment options are limited by an incomplete understanding of the mechanisms underlying de novo donor-specific antibody (DSA) generation. The development of pathogenic isotype-switched DSA in response to transplanted allografts is typically attributed to follicular B cells undergoing germinal center reaction whereas the contribution of other B cell subsets has not been previously addressed. The current study investigated the role of recipient marginal zone B cells (MZ B cells) in DSA responses using mouse models of heart and renal allotransplantation. MZ B cells rapidly differentiate into antibody-secreting cells in response to allotransplantation. Despite the selective depletion of follicular B cells in heart allograft recipients, MZ B cells are sufficient for T-dependent IgM and early IgG DSA production. Furthermore, the presence of intact MZ B cell subset is required to support the generation of pathogenic isotype-switched DSA in renal allograft recipients containing donor-reactive memory helper T cells. These findings are the first demonstration of the role of MZ B cells in humoral alloimmune responses following solid organ transplantation and identify MZ B cells as a potential therapeutic target for minimizing de novo DSA production and AMR in transplant recipients.