TCR origin and specificity to environmental or self-antigens on distinct antigen-presenting cells determine peripheral Treg cell differentiation.

TCR origin and antigen recognition shape peripheral Treg cell differentiation, with TCRs from Treg cells more effectively inducing tolerance across diverse antigens.

• Why it matters: Understanding how TCR specificity influences Treg cell development is crucial for designing targeted immunotherapies that promote immune tolerance and prevent autoimmune diseases.
• What they did: Using CRISPR-based TCR editing of primary T cells and a large TCR panel, the study examined how TCRs recognizing self, microbial, or dietary antigens drive pTreg cell differentiation and phenotype, revealing distinct transcriptional programs linked to antigen type and APC interaction.
• The result: Findings show TCR origin and specificity determine Treg cell phenotype and function, highlighting the importance of antigen presentation context, and providing a foundation for TCR-based tolerogenic treatments.