Rabbit Anti-Human FOXP3 Polyclonal antibody

Impaired tolerance to innocuous particles during allergic asthma has been linked to increased plasticity of FoxP3(+) regulatory T cells (Tregs) reprogramming into pathogenic effector cells, thus exacerbating airway disease. However, failure of tolerance mechanisms is driven by Th2 inflammatory signals. Therefore, the in vivo role of canonical IL-4 receptor alpha (IL-4R alpha) signaling, an essential driver of Th2-type airway responses to allergens, on the regulatory function of FoxP3(+) Tregs in allergic asthma was explored. Here, we used transgenic Foxp3(cre)IL-4R alpha(-/lox) and littermate control mice to investigate the role of IL-4 and IL-13 signaling via Tregs in house dust mite-induced (HDM-induced) allergic airway disease. We sensitized mice intratracheally on day 0, challenged them on days 6-10, and analyzed airway hyperresponsiveness (AHR), airway inflammation, mucus production, and cellular profile on day 14. In the absence of IL-4R alpha responsiveness on FoxP3(+) Tregs, exacerbated AHR and airway inflammation were shown in HDM-sensitized mice. Interestingly, reduced induction of FoxP3(+) Tregs accompanied increased IL-33 alarmin production and type 2 innate lymphoid cell activation in the lung, exacerbating airway hyperreactivity and lung eosinophilia. Taken together, our findings indicate that IL-4R alpha-unresponsive FoxP3(+) Tregs result in exaggerated innate Th2-type, IL-33-dependent airway inflammation and a break intolerance during allergic asthma.

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, 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. 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 Bcl6(fl/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.