Natural antigen landscape shaping intestinal Treg cells: Self, diet, and microbiota

The gut represents a melting pot of distinct classes of antigens derived from self antigens, dietary components, and the commensal microbiota. To maintain tolerance to innocuous antigens while preserving the capacity to respond to potentially harmful microorganisms, the immune system has evolved tightly regulated mechanisms centered on the generation of Foxp3⁺ regulatory T (Treg) cells at mucosal surfaces. Although early insights into intestinal Treg development were largely derived from studies using model dietary antigens or selected microbial species, a substantial gap remains in our understanding of the natural antigen landscape that elicits Treg responses in vivo. In this review, we discuss recent advances based on TCR classification approaches that define intestinal Treg T cell receptor (TCR) responses according to in vivo antigen reactivity, and we highlight key future directions for elucidating the functional roles of antigen-presenting cell subsets and their associated peptide landscapes in shaping intestinal Treg biology.