Modification of host dendritic cells by microchimerism-derived extracellular vesicles generates split tolerance

Significance The induction of tolerance is still an ideal and largely unachieved goal in the transplantation and autoimmunity fields. Understanding natural allotolerance mechanisms could help realize this objective. In this study we found that maternal microchimerism generated “split” tolerance, stimulating classical alloreactivity (i.e., recognition of intact peptide/allo-MHC class II complexes by CD4 T cells), while silencing CD4 T cells responding to allopeptide in a self-MHC–restricted manner. These contrary activities could be attributed to the presence of separate antigenic microdomains with different costimulatory properties on the surface of a single host dendritic cell. The possibility that this state develops from interaction with a microchimerism-derived extracellular vesicle has important implications for cell biology, cancer immunotherapy, and molecular immunology.