Tissue-specific mediators of allergen-driven type 2 inflammation

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PROJECT SUMMARY Allergens are a class of innocuous environmental antigens that drive an inappropriate inflammatory immune response in susceptible individuals that is often characterized by type 2 cytokine production from helper T cells (Th2). Inhalation of allergens such as house dust mite leads to allergic inflammation of the lung, yet precisely how allergens drive a type 2 immune response in the lung tissue is not clear. We have previously demonstrated that Blimp-1 plays a central role in Th2 cell differentiation in the lung in response to inhaled allergens. However, administration of the same allergens subcutaneously does not require Blimp-1 for the formation of Th2 cells, suggesting the route of entry and the resident tissue specific immune cells determine the necessity for Blimp-1 in Th2 cell differentiation. We have found in response to inhaled antigens that IL-10 is a key cytokine that promotes Blimp-1 in Th2 cells. Blimp-1 acts by repressing Bcl6, itself a potent suppressor of the canonical transcription factor associated with Th2 cells, GATA3. Based on these data, we propose that unique signals driven by lung cells draining to the lymph node from the local tissue environment during T cell priming impact lung specific responses to allergens by promoting Blimp-1 and thus type 2 immunity. In this proposal we will 1) Determine how allergens support Blimp-1 and Th2 cells via IL-10 using an innovative technology that combines unbiased gene expression analysis with spatial location in the tissue to identify IL-10 producing cells in the lung and lymph nodes and their relationship to T cells expressing Blimp-1. In addition, we will 2) perform scRNAseq and scATACseq to identify how lung-specific environments established prior to allergic sensitization impact the immune response upon allergen challenge. We expect these studies to identify fundamental early steps in T cell priming in the lung draining lymph node in response to lung-derived allergens, demonstrating that tissue-specific environmental signals at homeostasis can shape subsequent immune responses to antigen challenge driving unique T cell differentiation pathways. In addition, our unbiased approaches have the potential to elucidate both the spatial location of early T cell priming pathways but also identify novel mediators that promote type 2 immunity to allergens. These studies therefore will have a fundamental impact on future studies that could identify potential therapeutic targets for the treatment of allergic asthma.