Microenvironment Matters: Unique Conditions Within Gut-Draining Lymph Nodes Favor Efficient De Novo Induction of Regulatory T Cells

The gastrointestinal tract constitutes the largest surface of the body and thus has developed multitude mechanisms to either prevent pathogen entry or to efficiently eliminate invading pathogens. At the same time, the gastrointestinal system has to avoid unwanted immune responses against self and harmless nonself antigens, such as nutrients and commensal microbiota. Therefore, it is somewhat not unexpected that the gastrointestinal mucosa serves as the largest repository of immune cells throughout the body, harboring both potent pro-as well as anti-inflammatory properties. One additional key element of this regulatory machinery is created by trillions of symbiotic commensal bacteria in the gut. The microbiota not only simply contribute to the breakdown of nutrients, but are essential in limiting the expansion of pathogens, directing the development of the intestinal immune system, and establishing mucosal tolerance by fostering the induction of regulatory T cells (Tregs). In this review, we will discuss our current understanding about the microenvironmental factors fostering the de novo generation of Tregs within the gastrointestinal immune system, focusing on unique properties of antigen-presenting cells, tolerogenic cytokines, commensal-derived metabolites and the contribution of lymph node stromal cells.