Title: The Beta Cell “Invisibility Cloak” – Insights into Immune Recognition and β-Cell Stress

Abstract: Type 1 diabetes (T1D) is an autoimmune disease characterized by the destruction of insulin-producing pancreatic β cells. Stem cell-derived islets (SCIs) offer a promising renewable source of β cells for transplantation; however, immune-mediated rejection remains a significant barrier to their therapeutic application. This research investigates two complementary approaches to understanding and overcoming immune-mediated β-cell destruction: engineering immune-evasive SCIs and examining how intrinsic β-cell stress influences immune susceptibility.

Using human T-cell co-culture models, we evaluated the immune-evasive properties of genetically engineered DKO;iCP SCIs, which lack HLA class I and II expression and inducibly express the immune-inhibitory proteins PD-L1 and CTLA4-Ig. Preliminary findings demonstrate reduced granzyme B secretion in DKO;iCP co-cultures compared with unmodified SCIs, suggesting enhanced resistance to T-cell-mediated cytotoxicity. Additionally, we investigated the effects of endoplasmic reticulum (ER) stress and T1D disease status on immune responses. Our findings suggest that T1D-derived T cells exhibit increased cytotoxic activity, while ER stress selectively enhances immune-mediated cytotoxicity in T1D-derived SCIs.

Together, these findings highlight the importance of both immune evasion and β-cell-intrinsic stress in developing more effective β-cell replacement therapies for T1D.

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