Microbiota- and diet-specific T cells become T _regs by default

CD4 ⁺ T cells recognize antigens from microbiota, diet, and pathogens via T cell receptors (TCRs) and orchestrate immunity by differentiating into tolerogenic regulatory (T _reg ) or pro-inflammatory effector (T _eff ) lineages (e.g. T _H 1 or T _H 17) ( 1 ). Dysregulation of these responses underlies numerous gastrointestinal inflammatory and infectious diseases ( 2–6 ). The prevailing paradigm suggests that individual microbes and dietary antigens drive distinct cell fates (e.g., segmented filamentous bacteria [SFB] induce T _H 17 cells ( 7 ) whereas Helicobacter hepaticus ( 8 ) and diet ( 9 ) induce T _regs ). However, the generality of this model is uncertain: several key organisms are atypical, and foundational studies often omitted a complex microbiome or a diverse polyclonal TCR repertoire. Here we develop a high-throughput pipeline to screen hundreds of TCRs from mice colonized from birth with a 116-strain human microbiota (hCom2v), demonstrating that TCRs recognizing microbiota or dietary antigens are overwhelmingly enriched in the induced T _reg (iT _reg ) lineage. Endogenous CD4 ⁺ T cells specific for these antigens adopt a uniform iT _reg phenotype in vivo , both in hCom2v-colonized and conventional mice. This baseline tolerance is robust to acute inflammation but breaks down following a “two-hit” combination of inflammation and genetic susceptibility, allowing T _eff to emerge against otherwise T _reg -restricted antigens. These data support a revised paradigm in which antigen-specific T _reg induction is the default response to foreign antigens in the healthy gut, and effector responses are an exception reflecting a perceived threat. Reframing gastrointestinal immunity as a tolerance-first system provides a framework for understanding inflammatory disease pathogenesis and suggests that therapeutic strategies should aim to restore a T _reg -predominant baseline.