Effector memory-type regulatory T cells display phenotypic and functional instability.

Area of Science:

• Immunology
• Cell Therapy
• Genomic Medicine

Background:

• Regulatory T cells (Treg) are vital for immune homeostasis and hold therapeutic potential for immune disorders.
• Advancements in CAR technology and gene editing offer enhanced Treg specificity and function.
• Challenges remain in ensuring the safety and stability of gene-edited Treg products due to impurities and functional instability.

Purpose of the Study:

• To investigate the characteristics and stability of distinct Treg subsets.
• To identify Treg subsets suitable for developing safe and effective cell therapies.
• To optimize manufacturing processes for stable Treg cell products.

Main Methods:

• Analysis of Treg subset fate, epigenomic stability, transcriptomes, TCR repertoires, and function ex vivo.
• Evaluation of Treg subsets post-manufacturing.
• Depletion of specific Treg subsets prior to manufacturing.

Main Results:

• Each Treg subset exhibited unique features in lineage stability, epigenomics, surface markers, TCR diversity, and transcriptomics.
• Earlier-differentiated memory Treg subsets, including a novel naive-like memory Treg population, demonstrated superior regulatory function, proliferation, and epigenomic stability compared to late-differentiated effector memory Treg cells.
• High yields of stable, functional Treg products were achieved by excluding the effector memory-like Treg subset.

Conclusions:

• Treg subset composition is critical for maintaining lineage stability in cell products.
• Earlier-differentiated Treg subsets are more suitable for therapeutic applications due to enhanced stability and function.
• Depleting specific Treg subsets can improve the quality and efficacy of Treg-based cell therapies.