Human stem cell-derived β cells expressing an optimized CD155 reduce cytotoxic immune cell function for application...

Area of Science:

• Immunology
• Endocrinology
• Regenerative Medicine

Background:

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

Purpose of the Study:

• To engineer human pluripotent stem cells for enhanced immune evasion of sBC.
• To investigate the role of CD155-TIGIT signaling in protecting sBC from immune destruction.

Main Methods:

• Human pluripotent stem cells were engineered to express wild-type or high-affinity mutant CD155.
• Engineered cells were differentiated into sBC and co-cultured with immune cells.
• Immune cell activation, sBC destruction, and cytotoxic molecule secretion were assessed, with and without TIGIT blockade.

Main Results:

• CD155-expressing sBC suppressed autoreactive CD8+ T cell and NK cell activation.
• Engaging the TIGIT receptor mediated this suppression, reducing immune cell-mediated sBC destruction.
• TIGIT blockade abolished the protective effect, confirming the CD155-TIGIT pathway's role.

Conclusions:

• High-affinity CD155 expression enhances sBC immune evasion.
• This strategy improves sBC survival and holds potential for T1D cell replacement therapy.