Extrathymically generated regulatory T cells control mucosal T _H 2 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. Regulatory T (T _reg) cells prevent systemic and tissue-specific autoimmunity and inflammatory lesions at mucosal interfaces. These cells are generated in the thymus (tT _reg cells) and in the periphery (induced (i)T _reg cells), and their dual origin implies a division of labour between tT _reg and iT _reg cells in immune homeostasis. Here we show that a highly selective blockage in differentiation of iT _reg cells in mice did not lead to unprovoked multi-organ autoimmunity, exacerbation of induced tissue-specific autoimmune pathology, or increased pro-inflammatory responses of T helper 1 (T _H 1) and T _H 17 cells. However, mice deficient in iT _reg cells spontaneously developed pronounced T _H 2-type pathologies at mucosal sites-in the gastrointestinal tract and lungs-with hallmarks of allergic inflammation and asthma. Furthermore, iT _reg-cell deficiency altered gut microbial communities. These results suggest that whereas T _reg cells generated in the thymus appear sufficient for control of systemic and tissue-specific autoimmunity, extrathymic differentiation of T _reg cells affects commensal microbiota composition and serves a distinct, essential function in restraint of allergic-type inflammation at mucosal interfaces.