Specialized Dendritic Cells Mediating Peripheral Tolerance to Intestinal Antigens

The immune system is tasked with mounting effective responses to pathogens while preventing inflammation triggered by innocuous antigens, including those derived from self, food, and commensal microbes. This balance is especially critical in the intestine, where dietary and microbial antigens are constantly encountered. Peripherally induced regulatory T cells (pTreg or iTreg) play a key role in suppressing inappropriate immune activation and maintaining gut homeostasis. Elucidating how pTreg cells are generated along the gastrointestinal tract is therefore critical to understanding peripheral tolerance. Recent studies have revealed that intestinal antigen-specific pTreg cell differentiation is induced by a distinct lineage of antigen-presenting cells (APCs) requiring expression of the transcription factors RORγt and PRDM16. Genetic perturbation of these APCs results not only in microbiota-specific proinflammatory T cell responses but also in the breakdown of oral tolerance, which in turn predisposes to allergic inflammation. In this review, we summarize the discovery of these tolerance-inducing APCs, highlight their role in instructing pTreg cell differentiation in response to microbiota and dietary antigens, and discuss the regulatory networks that support their function during intestinal immune tolerance.