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 show promise for treating type 1 diabetes (T1D), but challenges such as donor shortages and immune rejection persist. Stem cell-derived β cells (sBC) provide a renewable source but remain susceptible to immune attack. We engineered human pluripotent stem cells to express either the wild type (WT) or a high-affinity mutant (Mut) variant (rs1058402, G>A; Ala⁶⁷Thr) of the natural killer (NK) and T cell checkpoint inhibitor CD155 before differentiation into sBC. Modified sBC maintained up-regulated CD155 expression and showed enhanced binding to co-receptor ligands. Co-culture studies revealed CD155-expressing sBC suppressed autoreactive CD8⁺ T cell and NK cell activation, reducing immune cell-mediated sBC destruction and cytotoxic molecule secretion by preferentially engaging the coinhibitory receptor TIGIT. This protection was lost with TIGIT blockade, affirming the role of CD155-TIGIT signaling in antagonizing immune cell cytotoxicity. Our findings suggest that high-affinity CD155 expression enhances immune evasion of sBC, improving their potential as a therapy for T1D.