This study examined how TCR origin and antigen specificity (self, microbial, or dietary) shape peripheral regulatory T (pTreg) cell differentiation, using CRISPR-based TCR editing of primary T cells with a large TCR panel across distinct antigen-presenting cell (APC) contexts.
All antigen classes (self, microbial, dietary) drove stable pTreg cell differentiation; TCRs from Treg cells were more effective than those from conventional T cells. Antigen class determined distinct phenotypes—self-reactive TCRs induced Helios⁺ pTregs via conventional dendritic cells, food-reactive TCRs induced RORγ⁺ pTregs via RORγ⁺ APCs, and some TCRs produced dual Helios⁺RORγ⁺ cells—each with distinct transcriptional programs.
The study relies on CRISPR-edited primary T cells with a curated TCR panel, which may not fully reflect the natural diversity of the TCR repertoire in vivo. The generalizability of findings to human immunology is not directly established, as the work appears primarily mechanistic/murine.
TCR specificity and APC context jointly govern pTreg phenotype, suggesting that TCR selection and antigen-presenting cell targeting are both critical variables when designing TCR-based tolerogenic immunotherapies for food allergy, autoimmunity, or microbiome-related tolerance.
Explore related topics
