Asthma is a chronic inflammatory lung disease afflicting millions of people showing increased incidence over the past decade. This T cell-mediated disease in allergic asthma is typically thought of as a type 2/Th2 disease, yet precisely how the environmental antigens that trigger asthma initiate Th2 cell development in the lung is unknown. In this application, we describe Blimp-1 as an unexpected regulator of allergen-induced airway inflammation that is critical to promote Th2 cell development in the lung and subsequent airway inflammation. Blimp-1 is a transcriptional repressor that is pleiotropically expressed by effector T cells, and whose role is to regulate effector T cell responses and constrain T cell-mediated autoimmunity. Our recently published work (Science Immunology 2016) has demonstrated that the anti-inflammatory cytokine IL-10 acting through STAT3 is sufficient to induce Blimp-1 in Th2 cells both in vitro and in vivo. Herein, we propose that another STAT3-activating cytokine, IL-6, previously shown to promote allergic experimental asthma downstream of c-kit on dendritic cells, induces Blimp-1 in Th2 cells to initiate Th2 cell development by a hitherto unappreciated mechanism involving effects on Bcl6 and GATA-3, which in turn promotes allergic airway inflammation. We will test our hypothesis in two aims. We will test the prediction that 1) STAT3 is a critical proximal signal that regulates Blimp-1 in Th2 cells during allergic airway disease to suppress Bcl6 and upregulate GATA-3 in T cells, and 2) Blimp-1 is an essential transcriptional regulator that drives pathological Th2 cells during allergic airway inflammation. These studies will elucidate a paradoxical role of Blimp-1 in T cells to either promote or constrain effector T cell responses depending on the context and potentially uncover a novel mechanism linking IL-6 to induction of Th2 cells through expression of Blimp-1. Besides its role in Th2 differentiation, GATA-3 also has an essential role in thymic T cell development, therefore targeting GATA-3 can be expected to have broad effects. The present study is significant because of its potential to establish a novel therapeutic target, Blimp-1, to specifically blunt Th2 cell generation and disease without being broadly immunosuppressive.
The proposed research is relevant for human health and disease because allergic asthma has limited treatment options and is currently on the rise in the United States, therefore there is a need to understand the mechanisms that initiate disease in order to identify new targets for the development of therapeutic options. Our proposal has identified a new factor, Blimp-1, that contributes to the development of allergic asthma disease by promoting the development of the pathogenic T cell type known to drive inflammation of the lung and subsequent airway inflammation and disease. Therefore, this research has translational significance for patients with asthma while also elucidating basic mechanisms of the pathogenesis of allergic disease and T cell responses to allergens.
