Human Stem Cell-Derived β-cells Expressing An Optimized CD155 Reduce Cytotoxic Immune Cell Function for Application in Type 1 Diabetes.

Insulin-producing β-cell replacement therapies offers a potential treatment for type 1 diabetes (T1D) but faces challenges from donor shortages and immune rejection. Stem cell-derived β-cells (sBC) provide a renewable source but remain vulnerable to immune attack. We engineered human pluripotent stem cells to express either the wildtype (WT) or a high-affinity mutant (Mut) variant (rs1058402, G>A; Ala67Thr) of the NK and T cell checkpoint inhibitor CD155 before differentiation into sBC. Modified sBC maintained upregulated CD155 expression and showed enhanced binding to co-receptor ligands. Co-culture studies revealed that CD155 Mut-expressing sBC suppressed CD8(+) T cell and NK cell activation and proliferation by preferentially engaging the co-inhibitory receptor TIGIT. Both CD155 Mut sBC lines reduced autoreactive CD8(+) T cell- and NK cell-mediated sBC destruction and cytotoxic molecule secretion. This protection was lost with TIGIT blockade, confirming the role of CD155-TIGIT signaling in antagonizing immune cell-mediated killing. Our findings suggest that high-affinity CD155 expression enhances immune evasion of sBC, improving their potential for restorative therapy in T1D.