Extrathymically generated regulatory T cells control mucosal TH2 inflammation

Nature. 2012 Feb 8;482(7385):395-9. doi: 10.1038/nature10772.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Asthma / immunology
  • Asthma / pathology
  • Cell Differentiation
  • Enhancer Elements, Genetic / genetics
  • Female
  • Forkhead Transcription Factors / genetics
  • Immunity, Mucosal / immunology*
  • Inflammation / immunology*
  • Inflammation / pathology
  • Intestines / immunology
  • Intestines / microbiology
  • Intestines / pathology
  • Lung / immunology
  • Lung / pathology
  • Male
  • Mice
  • Organ Specificity
  • Stomach / immunology
  • Stomach / microbiology
  • Stomach / pathology
  • T-Lymphocytes, Regulatory / cytology*
  • T-Lymphocytes, Regulatory / immunology*
  • Th2 Cells / immunology*
  • Thymus Gland


  • Forkhead Transcription Factors
  • Foxp3 protein, mouse