Research ArticleTransplantation

Graft-derived extracellular vesicles transported across subcapsular sinus macrophages elicit B cell alloimmunity after transplantation

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Science Translational Medicine  17 Mar 2021:
Vol. 13, Issue 585, eabb0122
DOI: 10.1126/scitranslmed.abb0122

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An extra source of donor antigen

B cell alloimmunity is a major driver of transplant rejection. Allospecific B cells become activated after exposure to donor antigens and begin producing donor-specific antibodies that cause rejection. Here, Zeng et al. investigated the mechanisms by which donor antigens come in proximity to alloreactive B cells. The authors showed, using flow cytometry and two-photon microscopy, that extracellular vesicles released by skin or cardiac grafts drain to secondary lymphoid tissues and are captured by flypaper-like subcapsular sinus macrophages in lymph nodes and analogue macrophages in the spleen. The subcapsular sinus macrophages in turn passed antigen to alloreactive B cells, which became activated and produced donor-specific antibodies. Thus, targeting graft-derived extracellular vesicles may be a strategy to combat allograft rejection.

Abstract

Despite the role of donor-specific antibodies (DSAs) in recognizing major histocompatibility complex (MHC) antigens and mediating transplant rejection, how and where recipient B cells in lymphoid tissues encounter donor MHC antigens remains unclear. Contrary to the dogma, we demonstrated here that migration of donor leukocytes out of skin or heart allografts is not necessary for B or T cell allosensitization in mice. We found that mouse skin and cardiac allografts and human skin grafts release cell-free donor MHC antigens via extracellular vesicles (EVs) that are captured by subcapsular sinus (SCS) macrophages in lymph nodes or analog macrophages in the spleen. Donor EVs were transported across the SCS macrophages, and donor MHC molecules on the EVs were recognized by alloreactive B cells. This triggered B cell activation and DSA production, which were both prevented by SCS macrophage depletion. These results reveal an unexpected role for graft-derived EVs and open venues to interfere with EV biogenesis, trafficking, or function to restrain priming or reactivation of alloreactive B cells.

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