Building tolerance: employing genome engineering toward universal Treg therapy

Area of Science:

• Immunology
• Cell Biology
• Genetic Engineering

Background:

• Regulatory T cells (Tregs) are crucial for immune homeostasis and preventing autoimmune diseases.
• The development of universal, allogeneic Treg therapies is hindered by immune rejection.
• Genome editing offers a potential solution to overcome Treg immunogenicity.

Purpose of the Study:

• To engineer genome-edited Tregs that evade immune rejection while maintaining suppressive function.
• To assess the efficacy of these modified Tregs in promoting graft tolerance.
• To discuss the potential and challenges of universal "off-the-shelf" Treg therapies.

Main Methods:

• Non-viral CRISPR-Cas9 genome editing was used to modify Tregs.
• Key genes (B2M, CIITA) were deleted, and an HLA-E-B2M fusion was inserted.
• Hypo-immunogenic Tregs were generated and tested in humanized mouse models.

Main Results:

• Genome-edited Tregs demonstrated reduced immunogenicity.
• Modified Tregs persisted and promoted graft tolerance in humanized mice.
• The engineered Tregs retained their immune suppressive function.

Conclusions:

• Genome engineering can create hypo-immunogenic Tregs for universal therapeutic use.
• These "off-the-shelf" Tregs represent a significant advancement in programmable immune tolerance.
• Further research is needed to address challenges for clinical translation.