Donor-reactive T cells and innate immune cells promote pig-to-human decedent xenograft rejection

Xenotransplantation of pig organs is a promising solution to the organ shortage; however, rejection remains a major obstacle. Pig-to-human decedent transplantation provides an opportunity to study immune barriers to xenotransplantation experimentally. We tracked donor-reactive T cell dynamics in a 61-day pig-to-human decedent thymokidney xenotransplant. Xenogeneic donor-reactive T cell clones (XDRTCCs) identified using high-throughput TCRB CDR3 sequencing expanded markedly in peripheral blood in association with apparent antibody-mediated rejection (AMR). Single-cell RNA and TCR sequencing of leukocytes from the xenograft showed XDRTCC infiltration and effector transcript expression during AMR. Additionally, γδ and NK cells with cytotoxic effector phenotypes were prominent in the rejecting xenograft. These data suggest that improved suppression of innate immunity and T cell responses might enhance the success of xenotransplantation.