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

Abstract

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. 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. We used a model of house dust mite sensitization to challenge wild-type, Bcl6^fl/fl Foxp3-Cre, and Prdm1 (Blimp1)^fl/fl Foxp3-Cre mice to study the reciprocal roles of Bcl6 and Blimp1 in allergic airway inflammation. 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 Bcl6^fl/fl Foxp3-Cre mice. 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.