Extrathymically generated regulatory T cells control mucosal TH2 inflammation

Top Cited Papers
Publisher Website
Google Scholar
Abstract
Selective impairment of peripheral regulatory T-cell differentiation is found to result in spontaneous allergic TH2-type inflammation in the intestine and lungs, demonstrating the functional heterogeneity of regulatory T cells generated in the thymus and extrathymically in controlling immune mediated inflammation and disease. Regulatory T (Treg) cells generated in the periphery are shown to have a distinct non-redundant function compared with Treg cells that differentiate in the thymus. Selective impairment of peripheral Treg differentiation results in spontaneous allergic TH2 type inflammation in the intestine and lungs. This study in mice delineates the functional heterogeneity of Treg cells in controlling systemic mucosal inflammation and disease. 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 inflammation1. Regulatory T (Treg) cells prevent systemic and tissue-specific autoimmunity and inflammatory lesions at mucosal interfaces. These cells are generated in the thymus (tTreg cells) and in the periphery (induced (i)Treg cells), and their dual origin implies a division of labour between tTreg and iTreg cells in immune homeostasis. Here we show that a highly selective blockage in differentiation of iTreg 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 (TH1) and TH17 cells. However, mice deficient in iTreg cells spontaneously developed pronounced TH2-type pathologies at mucosal sites—in the gastrointestinal tract and lungs—with hallmarks of allergic inflammation and asthma. Furthermore, iTreg-cell deficiency altered gut microbial communities. These results suggest that whereas Treg cells generated in the thymus appear sufficient for control of systemic and tissue-specific autoimmunity, extrathymic differentiation of Treg cells affects commensal microbiota composition and serves a distinct, essential function in restraint of allergic-type inflammation at mucosal interfaces.