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

Area of Science:

• Immunology
• Stem Cell Biology
• Endocrinology

Background:

• Type 1 diabetes (T1D) treatment faces challenges with donor shortages and immune rejection of beta-cell replacement therapies.
• Stem cell-derived beta-cells (sBC) offer a renewable source but are vulnerable to immune destruction.

Purpose of the Study:

• To engineer human pluripotent stem cells to express a high-affinity mutant (Mut) variant of the immune checkpoint inhibitor CD155.
• To evaluate the ability of modified sBC to evade immune attack mediated by T cells and NK cells.

Main Methods:

• Human pluripotent stem cells were engineered to express wildtype (WT) or high-affinity mutant (Mut) CD155.
• Modified cells were differentiated into sBC, and their immune interaction was assessed via co-culture studies.
• The role of CD155-TIGIT signaling in immune evasion was confirmed using TIGIT blockade.

Main Results:

• CD155 Mut-expressing sBC demonstrated upregulated CD155 and enhanced ligand binding.
• CD155 Mut sBC suppressed CD8+ T cell and NK cell activation and proliferation by engaging TIGIT.
• sBC expressing CD155 Mut showed reduced destruction by autoreactive immune cells and lower cytotoxic molecule secretion.

Conclusions:

• High-affinity CD155 expression enhances immune evasion of sBC by utilizing the CD155-TIGIT inhibitory pathway.
• This engineered immune evasion mechanism improves the therapeutic potential of sBC for type 1 diabetes.
• Targeting CD155-TIGIT signaling represents a novel strategy for protecting beta-cell therapies from immune attack.