Bcl6 is required for the development of T follicular helper and regulatory (Tfh, Tfr) cells that regulate germinal center responses. Bcl6 also impacts the function of regulatory T (Treg) cells.
The goal of this study is to define the functions of Bcl6 in Treg cells including Tfr cells in the context of allergic airway inflammation (AAI).
We employed a model of house dust mite (HDM) 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 AAI.
In the HDM 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)+ Tregs develop as observed in wild type mice. ST2+ Tregs in the context of AAI are Blimp1-dependent, express type 2 cytokines, and share features of visceral adipose tissue Treg cells. Bcl6-deficient Tregs are more susceptible, and Blimp1-deficient Tregs are resistant, to acquiring the ST2+ Treg cell phenotype in vitro and in vivo in response to IL-33. Bcl6-deficient ST2+ Tregs but not Bcl6-deficient ST2+ T conventional cells strongly promote AAI when transferred into recipient mice. Lastly, ST2 is required for the exacerbated AAI in Bcl6fl/fl Foxp3-Cre mice.
During AAI, Bcl6 and Blimp1 play dual roles in regulating Tfr activity in the germinal center and in the development of ST2+ Tregs that promote type 2 cytokine responses.