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. 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.
Howard Hughes Medical Institute and Immunology Program, Sloan Kettering Institute, New York, New York 10021, USA.
Steven Z
SZ
Josefowicz
Rachel E
RE
Niec
Hye Young
HY
Kim
Piper
P
Treuting
Takatoshi
T
Chinen
Ye
Y
Zheng
Dale T
DT
Umetsu
Alexander Y
AY
Rudensky
D000818:Animals; D001249:Asthma / Q000276:immunology / Q000473:pathology; D002454:Cell Differentiation; D004742:Enhancer Elements, Genetic / Q000235:genetics; D005260:Female; D051858:Forkhead Transcription Factors / Q000235:genetics; D018928:Immunity, Mucosal / Q000276:immunology*; D007249:Inflammation / Q000276:immunology* / Q000473:pathology; D007422:Intestines / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D008168:Lung / Q000276:immunology / Q000473:pathology; D008297:Male; D051379:Mice; D009928:Organ Specificity; D013270:Stomach / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D050378:T-Lymphocytes, Regulatory / Q000166:cytology* / Q000276:immunology*; D018418:Th2 Cells / Q000276:immunology*; D013950:Thymus Gland
D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse