Xenotransplantation offers a promising solution to the shortage of human donor organs, with pigs representing the preferred donor species due to their anatomical compatibility and suitability for genetic engineering. This thesis investigates how human immune cells interact with porcine aortic endothelial cells (PAECs), the first cellular interface encountered after transplantation, and how targeted genetic modifications can reduce graft immunogenicity. Using live-cell imaging under static and 3D-flow conditions, the study demonstrates that endothelial activation increases natural killer (NK) cell adhesion, migration, and cytotoxic interactions with PAECs. Expression of human CD47 on PAECs modestly reduces NK-mediated injury, highlighting the importance of adhesion dynamics in acute innate immune responses. The thesis further examines human cytotoxic T lymphocyte (CTL) responses to genetically modified PAECs lacking swine leukocyte antigen class I (B2M-KO) or expressing human PD-L1. Loss of antigen presentation markedly suppresses CD8⁺ T-cell expansion and antigen-specific cytotoxicity, whereas PD-L1 primarily attenuates immune synapse activity without abolishing specificity. Finally, translational studies in baboon models reveal substantial species-specific differences in immune phenotyping, emphasizing the need for validated immunomonitoring tools in xenotransplantation research. Together, these findings provide a framework for engineering pig grafts that reduce immune injury while limiting the need for systemic immunosuppression.