Overexpression of CD155 in human stem cell-derived β-cells diminishes autoreactive T cell responses 4558

Abstract Description Improved methods for generating human pluripotent stem cell (hPSC)-derived cells have rapidly expanded the field of regenerative medicine, holding extreme promise for treating diseases like type 1 diabetes, where stem cell-derived beta-cells (sBC) represent a possible therapeutic intervention. However, sBC need to be protected, ideally in a localized manner, from an antagonistic host immune response. Here, we engineered hPSC to overexpress either a wildtype (WT) or high affinity mutant (rs1058402; G>A; Ala67Thr) (Mut) version of the checkpoint inhibitor CD155, which binds to TIGIT on T cells to suppress effector function. Engineered CD155 overexpressing hPSCs retain pluripotent stem cell markers and efficiently differentiate into functional stem cell-derived beta cells (sBC), compared to the unmodified hPSC. Compared to CD155 WT cells, CD155 Mut sBC displayed increased TIGIT-Ig and CD226-Ig binding affinity and suppressed the proliferation of allogeneic CD8+ T cells. CD155 WT and Mut overexpression restrained the secretion of cytolytic effector molecules and autoreactive human CD8+ T cell avatar-mediated sBC killing compared to control sBC, with further inhibition seen in the CD155 Mut sBC cultures. This protective effect was abrogated in the presence of TIGIT blockade.Collectively, we provide evidence that high affinity CD155 expressed on sBC reduces autoreactive CD8+ T cell cytotoxicity and may confer localized immune protection to transplanted beta cells. Funding Sources Supported by NIH R01DK12044, NIH R01DK132387, Breakthrough T1D 2-SRA-2023-1313-S-B, and Breathrough T1D 3-SRA-2023-1367-S-B Topic Categories Transplantation Immunology (TRAN)