Lung-specific expression and function of Blimp-1 in T cells impacting allergic asthma

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PROJECT SUMMARY Allergic asthma is a chronic inflammatory disease of the lung that drives a type 2 cytokine response (such as IL- 4, IL-5, and IL-13) predominately produced by activated CD4 T cells of a Th2 phenotype in response to exposure with environmental allergens. The master transcription factor GATA3 is known to drive Th2 development and promote type 2 cytokine production, however, the molecular pathways that drive Th2 cells to allergens at both the initiation and recall stages are not well understood. We have reported that Blimp-1 is an unexpected driver of allergic asthma 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 can regulate effector cell responses to constrain T cell-mediated autoimmunity. The purpose of this proposal is to understand the tissue-specific environmental niche of the lung that promotes Blimp-1 expression to drive Th2 development in the lung and subsequent inflammation in response to allergens. We have shown that the IL-10- STAT3-Blimp-1 axis is critical for Blimp-1 to promote Th2 cells in response to inhaled allergens. We now hypothesize that inhalation of allergens creates a lung-specific inflammatory environment to promote Blimp-1 and drive differentiation Th2 cells in both primary and memory responses to allergen leading to cycle of chronic lung inflammation. We will explore this hypothesis in three aims: (1) Demonstrate that expression of Blimp-1 requires IL-10 from lung-derived migratory cDC2s produced in response to inhaled allergens. (2) Determine if the kinetics of Blimp-1 expression in T cells underlie its context-dependent function to drive Th2 differentiation or constrain effector T cells. (3) Demonstrate that allergen-specific memory T cells require Blimp-1 for Th2 driven recall responses in the lung. Overall, we will determine the role of Blimp-1 in de novo generation of Th2 cells to drive a type 2 niche and promote persistent inflammation. This study is significant because of its potential to identify pathways regulating Th2 cells in response to chronic allergens, as well as to elucidate the context- dependent function of Blimp-1, an important regulator of effector T cell differentiation and function. This work therefore will demonstrate how tissue-specific and context-dependent immunity must be considered in therapeutic approaches for diseases associated with tissues such as allergic asthma.