Bcl6 and Blimp1 reciprocally regulate ST2+ Treg–cell development in the context of allergic airway inflammation

Byunghee Koh, Benjamin J. Ulrich, Andrew S. Nelson, Gayathri Panangipalli, Rakshin Kharwadkar, Wenting Wu, Markus M. Xie, Yongyao Fu, Matthew J. Turner, Sophie Paczesny, Sarath Chandra Janga, Alexander L. Dent, Mark H. Kaplan

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Abstract

Background: Bcl6 is required for the development of T follicular helper cells and T follicular regulatory (Tfr) cells that regulate germinal center responses. Bcl6 also affects the function of regulatory T (Treg) cells. Objective: The goal of this study was to define the functions of Bcl6 in Treg cells, including Tfr cells, in the context of allergic airway inflammation. Methods: We used a model of house dust mite sensitization to challenge wild-type, Bcl6fl/fl Foxp3-Cre, and Prdm1 (Blimp1)fl/fl Foxp3-Cre mice to study the reciprocal roles of Bcl6 and Blimp1 in allergic airway inflammation. Results: In the house dust mite model, Tfr cells repress the production of IgE and Bcl6+ Treg cells suppress the generation of type 2 cytokine–producing cells in the lungs. In mice with Bcl6-deficient Treg cells, twice as many ST2+ (IL-33R+) Treg cells develop as are observed in wild-type mice. ST2+ Treg cells in the context of allergic airway inflammation are Blimp1 dependent, express type 2 cytokines, and share features of visceral adipose tissue Treg cells. Bcl6-deficient Treg cells are more susceptible, and Blimp1-deficient Treg cells are resistant, to acquiring the ST2+ Treg–cell phenotype in vitro and in vivo in response to IL-33. Bcl6-deficient ST2+ Treg cells, but not Bcl6-deficient ST2+ conventional T cells, strongly promote allergic airway inflammation when transferred into recipient mice. Lastly, ST2 is required for the exacerbated allergic airway inflammation in Bcl6fl/fl Foxp3-Cre mice. Conclusions: During allergic airway inflammation, Bcl6 and Blimp1 play dual roles in regulating Tfr-cell activity in the germinal center and in the development of ST2+ Treg cells that promote type 2 cytokine responses.

Original languageEnglish (US)
JournalJournal of Allergy and Clinical Immunology
DOIs
StateAccepted/In press - Jan 1 2020

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Keywords

  • allergy
  • asthma
  • Bcl6
  • Blimp1
  • Interleukin-33
  • ST2
  • ST2-expressing regulatory T cells
  • T follicular regulatory T cells

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Koh, B., Ulrich, B. J., Nelson, A. S., Panangipalli, G., Kharwadkar, R., Wu, W., Xie, M. M., Fu, Y., Turner, M. J., Paczesny, S., Janga, S. C., Dent, A. L., & Kaplan, M. H. (Accepted/In press). Bcl6 and Blimp1 reciprocally regulate ST2+ Treg–cell development in the context of allergic airway inflammation. Journal of Allergy and Clinical Immunology. https://doi.org/10.1016/j.jaci.2020.03.002