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

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.

Extracellular Vesicles in Transplantation

“…These changes are certainly linked to a function of the EV compartment in the process of graft rejection. EVs are a potent intermediate that promotes contact between donor antigens and the host immune system, as they are enriched in MHC and costimulatory molecules for most types of transplant rejection (139,(141)(142)(143).…”

Extracellular Vesicles From Kidney Allografts Express miR-218-5p and Alter Th17/Treg Ratios

“…Gunasekaran et al showed expression of donor HLA and lung associated self-antigens on EV from serum and bronchoalveolar lavage fluid of lung transplant recipients with acute rejections but not in recipients with stable transplant ( 43 , 44 ). Few studies in various transplant models have shown that transfer of donor HLA to recipient APCs via EV is involved in the perpetuation of alloresponses by T cells leading to graft dysfunction ( 14 , 37 , 45 ).…”

Optimization of Sentinel Lymph Node Imaging Methodology Using Anionic Liposome and Hyaluronidase

“…In particular, the uptake of these vesicles to SSM and MSM in LNs plays a key role in immune suppression or tolerance [27], whereas the role of MCM has not been reported yet [28]. However, another report revealed that allograft-derived extracellular vesicles enhanced the immunity in the donor, and then consequently induced the rejection of allograft [29]. The precise role of this PS-mediated uptake is currently controversial.…”