Decoding Peripheral Tolerance: TCR Rules for pTreg differentiation in the Gut

Area of Science:

• Immunology
• T cell biology
• Regulatory T cell differentiation

Background:

• Peripheral differentiation of regulatory T cells (pTregs) is crucial for immunological tolerance to non-self antigens like food and microbes.
• The roles of T cell receptor (TCR) recognition versus environmental cues in pTreg differentiation are not well understood.

Purpose of the Study:

• To investigate the impact of different antigens and TCR origins on pTreg differentiation.
• To explore the distinct pTreg phenotypes induced by self, microbial, and dietary antigens.

Main Methods:

• Utilized CRISPR-based TCR editing in primary T cells.
• Performed an in vivo screen of a large TCR panel to assess pTreg differentiation.
• Analyzed pTreg phenotypes (Helios+, RORγ+) induced by various antigens.

Main Results:

• All tested antigen classes (self, microbial, dietary) induced pTreg differentiation.
• TCRs derived from Tregs were significantly more effective at promoting pTreg differentiation than those from conventional T cells (Tconv).
• Distinct pTreg phenotypes were observed depending on the antigen class and TCR origin, linked to specific antigen-presenting cells.

Conclusions:

• Treg-derived TCRs preferentially drive tolerogenic cell fates, highlighting their potential for therapeutic applications.
• Understanding antigen-specific pTreg differentiation pathways can inform the development of novel tolerogenic therapies.