T cell fate is dictated by different antigen-presenting cells in response to dietary versus gut epithelial self-antigen.

Mechanisms governing T cell responses to food or microbes have been characterized, but whether they also regulate gut autoimmunity is unknown. We compared ovalbumin (OVA)-specific T cell fates using mice fed OVA, or expressing secreted (s), cytosolic (c), or transmembrane (tm) epithelial OVA. At baseline and after reovirus infection, T cell responses were comparable. However, helminth infection induced T helper 2 (Th2) cell polarization in sOVA and tmOVA but not cOVA or OVA-fed mice. BATF3+ antigen-presenting cells (APCs) were indispensable for CD4+ T cell proliferation only in cOVA mice, yet they drove regulatory T (Treg) cell differentiation across all epithelial OVA models. In contrast, antigen presentation by RORγt+MHC class II+ APCs was exclusively required for Treg cell induction by dietary OVA. These distinct APC dependencies correlated with susceptibility to pathology elicited by dietary versus epithelial self-antigens. Thus, antigen origin and presentation context together shape T cell fate, aiding predictions of gut immune outcomes.