Transmembrane protein 16F-chloride intracellular channel 1 interaction mediates recipient dendritic cell...

Donor dendritic cell (DC)-derived extracellular vesicles cross-decorate recipient DCs to trigger T cell allorecognition and transplant rejection. However, the mechanism mediating recipient DC cross-decoration is unclear. Here, we find Rab27a-expressing donor DCs migrate to recipient secondary lymphoid organs, and donor DC-specific Rab27a deletion decreases recipient conventional DC cross-decoration after heart transplantation in mice. Furthermore, Rab27a or Rab27b deficiency in donor DCs or endothelial cells, rather than fibroblasts, prolongs allograft survival. Through proteomic analyses, molecular docking, and coimmunoprecipitation, we identified an interaction between transmembrane protein 16 (TMEM16F) on acceptor DCs and chloride intracellular channel 1 (CLIC1) on donor DC-derived extracellular vesicles, and the anthelmintic drug niclosamide may interrupt TMEM16F-CLIC1 interactions and dampen acceptor DC cross-decoration and T cell activation triggered by cross-decorated DCs in vitro. Likewise, niclosamide therapy limits recipient conventional DC cross-decoration and suppresses alloresponses after transplantation. Collectively, these results suggest that TMEM16F-CLIC1 interaction mediates recipient DC cross-decoration after transplantation, and niclosamide can be repurposed for the prevention of acute rejection.