Extrathymically generated regulatory T cells control mucosal TH2 inflammation

Abstract

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.

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Figure 1: Impaired iT reg cell generation and altered composition of the peripheral T reg cell population in CNS1-deficient mice.
Figure 2: Paucity of iT reg cells results in T H 2 inflammation in the gastrointestinal tract.
Figure 3: iT reg cell deficiency leads to T H 2 type gastrointestinal pathology and altered microbial communities.
Figure 4: Unprovoked asthma-like airway pathology in CNS1-deficient mice.

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Acknowledgements

We thank T. Tedder for depleting CD20 antibody, R. Tudor for assistance interpreting lung pathology, P. DeRoos for assistance with Ig ELISA assays, B. Johnson for immunohistochemical expertise, Y. Chen for assistance with airway measurements, and E. Pamer, L. Lipuma, A. Gobourne and R. Khanin for help with analysis of intestinal microbiota. This work was supported by NIH MSTP grant GM07739 and NINDS grant 1F31NS073203-01 (R.E.N.), Strategic Young Researcher Overseas Visits Program for Accelerating Brain Circulation from Department of Microbiology and Immunology, Keio University School of Medicine (T.C.) and NIH grant R37 AI034206 (A.Y.R.). A.Y.R is an investigator with the Howard Hughes Medical Institute.

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S.Z.J., R.E.N. and H.Y.K. performed experiments and analysed data, with assistance from T.C. for tissue Ig ELISA experiments, and P.T. for immunohistochemistry and histopathology analysis. D.T.U., S.Z.J., R.E.N., H.Y.K, and A.Y.R designed and interpreted AHR experiments. Y.Z. generated CNS1- mice. S.Z.J., R.E.N. and A.Y.R. designed experiments and wrote the paper.

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Correspondence to Alexander Y. Rudensky.

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The authors declare no competing financial interests.

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Josefowicz, S., Niec, R., Kim, H. et al. Extrathymically generated regulatory T cells control mucosal TH2 inflammation. Nature 482, 395–399 (2012). https://doi.org/10.1038/nature10772

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