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An asthma-associated IL4R variant exacerbates airway inflammation by promoting conversion of regulatory T cells to TH17-like cells

Nature Medicine volume 22, pages 1013–1022 (2016)Cite this article

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Abstract

Mechanisms by which regulatory T (Treg) cells fail to control inflammation in asthma remain poorly understood. We show that a severe asthma-associated polymorphism in the gene encoding the interleukin (IL)-4 receptor alpha chain (Il4raR576) promotes conversion of induced Treg (iTreg) cells toward a T helper 17 (TH17) cell fate. This skewing is mediated by the recruitment by IL-4RαR576 of the growth-factor-receptor-bound protein 2 (GRB2) adaptor protein, which drives IL-17 expression by activating a pathway that involves extracellular-signal-regulated kinase, IL-6 and the transcription factor STAT3. Treg cell–specific deletion of genes that regulate TH17 cell differentiation, including Il6ra and RAR-related orphan receptor gamma (Rorc), but not of Il4 or Il13, prevented exacerbated airway inflammation in mice expressing Il4raR576 (hereafter referred to as Il4raR576 mice). Furthermore, treatment of Il4raR576 mice with a neutralizing IL-6-specific antibody prevented iTreg cell reprogramming into TH17-like cells and protected against severe airway inflammation. These findings identify a previously unknown mechanism for the development of mixed TH2–TH17 cell inflammation in genetically prone individuals and point to interventions that stabilize iTreg cells as potentially effective therapeutic strategies.

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Figure 1: Il4raR576 polymorphism promotes enhanced lung inflammation and AHR, and is associated with increased IL-17, IL-6 and IL-13 expression.
Figure 2: Defective formation and impaired suppressive function of Il4raR576 iTreg cells.
Figure 3: CCR6+ IL-17+ Il4R576 Treg cells show instability and compromised suppressive activity.
Figure 4: IL-4RαR576 activates GRB2-coupled MAPK.
Figure 5: Naive CD4+ Tconv cells from subjects with asthma bearing the IL4RR576 mutation show defective induction of iTreg cells and their skewing toward a TH17-like phenotype.
Figure 6: Treg cell lineage–specific deletion of Rorc reverses the aggravated airway inflammation in Il4raR576 mice.

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Acknowledgements

This work was supported by a National Institutes of Health grants R01 AI065617 (T.A.C.), U10HL098102 (W.P.) and U10HL109172 (W.P.). We thank E. Crestani, D. Schierembergg and A. Cunningham for help with patient recruitment, and H.C. Oettgen and L.-M. Charbonnier for their critical review of the manuscript.

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Authors and Affiliations

  1. Division of Immunology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA

    Amir Hossein Massoud, Louis-Marie Charbonnier, Wanda Phipatanakul & Talal A Chatila

  2. Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA

    Amir Hossein Massoud, Louis-Marie Charbonnier, Wanda Phipatanakul & Talal A Chatila

  3. Department of Molecular, Cell and Developmental Biology, University of California, Los Angeles, Los Angeles, California, USA

    David Lopez & Matteo Pellegrini

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  1. Amir Hossein Massoud
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Contributions

T.A.C. conceived of the project and directed the research; A.H.M. and T.A.C. designed the experiments and evaluated the data; W.P. provided blood samples from subjects with asthma and discussed results; A.M. performed the experiments and prepared the figures; L.-M.C. performed epigenetic studies; D.L. and M.P. performed gene expression profiling studies; and A.M. and T.A.C. wrote the manuscript.

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Correspondence to Talal A Chatila.

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Supplementary Figures 1–15 and Supplementary Tables 1–2 (PDF 8733 kb)

Supplementary Dataset 1

Gene expression profiles of CCR6– versus CCR6+ Treg cells collected from lungs of OVA-sensitized and challenged Il4R576 mice. (XLSX 1685 kb)

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Massoud, A., Charbonnier, LM., Lopez, D. et al. An asthma-associated IL4R variant exacerbates airway inflammation by promoting conversion of regulatory T cells to TH17-like cells. Nat Med 22, 1013–1022 (2016). https://doi.org/10.1038/nm.4147

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