Extrathymically generated regulatory T cells control mucosal Th2 inflammation

By Steven Z. Josefowicz, R. Niec, H. Y. Kim, P. Treuting, T. Chinen, Ye Zheng, D. Umetsu, Alexander Y. Rudensky. Nature, 2012

828 citations recorded by the source corpus.

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 (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.

Subfields: Immunology

View Paper: https://www.semanticscholar.org/paper/83e9a514b224fc13d7802652d4bc6c4f71a79c54

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Citations in the corpus

Homeostatic immunity and the microbiota (2017, neutral): “…available in PMC 2018 April 18. throughout the lifespan of the host and disruption of the homeostasis of these cells in the GI tract results in loss of oral tolerance and development of aberrant effector responses in the gut (Josefowicz et al., 2012b; Mucida et al., 2005; Worbs et al., 2006).”
Neuropilin 1 is expressed on thymus-derived natural regulatory T cells, but not mucosa-generated induced Foxp3+ T reg cells (2012, background): “CNS1-null mice display normal development of thymic nT reg cells, but have a severe impairment in the development of TGF-–dependent iT reg cells at mucosal surfaces (Zheng et al., 2010; Josefowicz et al., 2012).”
Role of the Microbiota in Immunity and inflammation (2014, background): “A current consensus is that optimal maintenance of tolerance to commensal and environmental antigens requires the combined effect of both thymically and GI-induced Treg (Cebula et al., 2013; Josefowicz et al., 2012a; Lathrop et al., 2011).”
Regulatory T Cells: Mechanisms of Differentiation and Function (2012, background): “The previously discussed CNS1, which contains binding sites for NFAT, RAR/RXR, and TGF-β-activated Smad3, is critical for the induction of Foxp3 in peripheral naive CD4+ T cells (180).”
TGF-β Activation and Function in Immunity (2013, background): “However, in older mice lacking iTregs, Th2-mediated pathology developed in the lung and intestine, with altered bacterial species detected in the gut (85).”
INTERLEUKIN-4- AND INTERLEUKIN-13-MEDIATED ALTERNATIVELY ACTIVATED MACROPHAGES: ROLES IN HOMEOSTASIS AND DISEASE (2013, positive): “In this model, mutation of the Foxp3 enhancer CNS1 in mice results in a lack of the normal complement of iTreg cells; these mice concurrently exhibit spontaneous airway hyperresponsiveness and type 2 immune inflammation in the lung, characterized by the increased presence of acidophilic macrophages,”