Brown Matthew E, Barra Jessie M, Pina Marcus R, Proia James, Brusko Todd M, Russ Holger A
bioRxiv. 2025 Aug 15:2025.08.12.669867. doi: 10.1101/2025.08.12.669867.
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.
Engineered β-cells with a mutant CD155 help evade immune attack, offering a promising therapeutic approach for type 1 diabetes.
产生胰岛素的β细胞替代疗法为1型糖尿病（T1D）提供了一种潜在的治疗方法，但面临着供体短缺和免疫排斥的挑战。干细胞衍生的β细胞（sBC）提供了一种可再生的来源，但仍然容易受到免疫攻击。我们对人类多能干细胞进行工程改造，使其在分化为sBC之前表达自然杀伤细胞和T细胞检查点抑制剂CD155的野生型（WT）或高亲和力突变体（Mut）变体（rs1058402，G>A；丙氨酸67苏氨酸）。经过修饰的sBC维持上调的CD155表达，并显示出与共受体配体的结合增强。共培养研究表明，表达CD155 Mut的sBC通过优先结合共抑制受体TIGIT来抑制CD8 + T细胞和自然杀伤细胞的激活和增殖。两个表达CD155 Mut的sBC系均减少了自身反应性CD8 + T细胞和自然杀伤细胞介导的sBC破坏以及细胞毒性分子的分泌。TIGIT阻断后这种保护作用丧失，证实了CD155-TIGIT信号在拮抗免疫细胞介导的杀伤中的作用。我们的研究结果表明，高亲和力CD155表达增强了sBC的免疫逃逸能力，提高了它们在T1D恢复性治疗中的潜力。
具有突变型CD155的工程化β细胞有助于逃避免疫攻击，为1型糖尿病提供了一种有前景的治疗方法。
