Prolongation of corneal xenotransplant survival by T‐cell vaccination‐induced T‐regulatory cells

Abstract: Background: Corneal xenotransplantation is an alternative approach for overcoming shortage of allograft in clinics. However, the mechanism of acute corneal xenograft rejection and the method of prolonging xenograft survival have not been well defined. Methods: In this study, we used an orthotopic corneal guinea pig‐to‐rat xenotransplantation model to study the effects of CD4 and CD8 T cells, T‐cell vaccination (TCV) and TCV‐induced T‐regulatory (Treg) cells on xenograft survival. Results: The acute rejection of xenografts occurred in untreated rats as early as 6 days post‐transplantation, while TCV significantly prolonged xenograft survival from 6–12 to 21–27 days. The lymph node cells of the TCV‐treated rats exhibited significant response to the anti‐guinea pig T cells and the responding cell populations contained two Treg cell subsets, CD4 + CD25 − and CD8 + CD28 − T cells, both of which lack expression of Foxp3. Adoptive transfer of CD8 + CD28 − T cells resulted in profound inhibition of corneal xenograft rejection, while transfer of CD4 + CD25 − T cells alone exhibited no significant inhibition. However, transfer of the CD4 + CD25 − and CD8 + CD28 − T‐cell mixture remarkably enhanced the in vivo protective activity against xenograft rejection. Conclusions: These data suggest that TCV induces the activation of specific Treg cell subsets, CD4 + CD25 − and CD8 + CD28 − T cells, which may act cooperatively to mediate prolongation of corneal xenograft survival. Therefore, TCV can be used as immunotherapy for suppression of acute xenograft rejection.