Open AccessGraft-derived extracellular vesicles transported across subcapsular sinus macrophages elicit B cell alloimmunity after transplantation
Author(s) -
Furong Zeng,
Zhizhao Chen,
Rao Chen,
William J. Shufesky,
Mohna Bandyopadhyay,
Geoffrey Camirand,
Martin H. Oberbarnscheidt,
Mara Sullivan,
Catherine J. Baty,
Minwei Yang,
M Zamorano Calderón,
Donna B. Stolz,
G. Erdö́s,
Roberta Pelanda,
Todd V. Brennan,
Sergio D. Catz,
Simon C. Watkins,
Adriana T. Larregina,
Adrián E. Morelli
Publication year - 2021
Publication title -
science translational medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.819
H-Index - 216
eISSN - 1946-6242
pISSN - 1946-6234
DOI - 10.1126/scitranslmed.abb0122
Subject(s) - alloimmunity , immunology , antigen , microbiology and biotechnology , major histocompatibility complex , transplantation , biology , medicine , surgery
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.