Extrathymically generated regulatory T cells control mucosal TH2 inflammation

A balance between pro- and anti-inflammatory mechanisms at mucosal interfaces, which are sites of constitutive exposure to microbes and non-microbial foreign substances, allows for efficient protection against pathogens yet prevents adverse inflammatory responses associated with allergy, asthma and intestinal inflammation (1). Regulatory T ([T.sub.reg]) cells prevent systemic and tissue-specific autoimmunity and inflammatory lesions at mucosal interfaces. These cells are generated in the thymus ([tT.sub.reg] cells) and in the periphery (induced (i)[T.sub.reg] cells), and their dual origin implies a division of labour between [tT.sub.reg] and [iT.sub.reg] cells in immune homeostasis. Here we show that a highly selective blockage in differentiation of [iT.sub.reg] cells in mice did not lead to unprovoked multiorgan autoimmunity, exacerbation of induced tissue-specific autoimmune pathology, or increased pro-inflammatory responses of T helper 1 ([T.sub.H]1) and [T.sub.H]17 cells. However, mice deficient in [iT.sub.reg] cells spontaneously developed pronounced [T.sub.H]2-type pathologies at mucosal sites--in the gastrointestinal tract and lungs--with hallmarks of allergic inflammation and asthma. Furthermore, [iT.sub.reg]-cell deficiency altered gut microbial communities. These results suggest that whereas [T.sub.reg] cells generated in the thymus appear sufficient for control of systemic and tissue-specific autoimmunity, extrathymic differentiation of [T.sub.reg] cells affects commensal micro-biota composition and serves a distinct, essential function in restraint of allergic-type inflammation at mucosal interfaces.