PD-L1 Promotes Immunological Tolerance and Enhances Visual Protection of hESC-RPE Grafts in Retinal Degeneration

Immune rejection is a major barrier to the successful human embryonic stem cell-derived retinal pigment epithelial (hESC-RPE) transplantation for age-related macular degeneration (AMD). Traditional strategies to mitigate immune rejection involve ablating major histocompatibility complex (MHC) molecules on hESC-RPE. An alternative approach is immune checkpoint overexpression, avoiding natural killer (NK) cell-mediated destruction due to MHC-I deficiency. Our study highlights the benefits of PD-L1 overexpression without requiring MHC gene deletion, which preserved the immunosuppressive functions of hESC-RPE on NK cells. In Vivo experiments in retinal degeneration models showed that PD-L1-expressing hESC-RPE grafts exhibited significantly higher survival, reduced apoptosis and enhanced visual protection. Single-cell transcriptomics revealed reduced immune activation and oxidative stress in PD-L1-overexpressing grafts. PD-L1's protective role was further evidenced by improved light transduction in host photoreceptors. These findings support PD-L1 overexpression as a promising strategy to improve the efficiency of hESC-RPE-based therapy for AMD.Immune rejection is a major barrier to the successful human embryonic stem cell-derived retinal pigment epithelial (hESC-RPE) transplantation for age-related macular degeneration (AMD). Traditional strategies to mitigate immune rejection involve ablating major histocompatibility complex (MHC) molecules on hESC-RPE. An alternative approach is immune checkpoint overexpression, avoiding natural killer (NK) cell-mediated destruction due to MHC-I deficiency. Our study highlights the benefits of PD-L1 overexpression without requiring MHC gene deletion, which preserved the immunosuppressive functions of hESC-RPE on NK cells. In Vivo experiments in retinal degeneration models showed that PD-L1-expressing hESC-RPE grafts exhibited significantly higher survival, reduced apoptosis and enhanced visual protection. Single-cell transcriptomics revealed reduced immune activation and oxidative stress in PD-L1-overexpressing grafts. PD-L1's protective role was further evidenced by improved light transduction in host photoreceptors. These findings support PD-L1 overexpression as a promising strategy to improve the efficiency of hESC-RPE-based therapy for AMD.