Asthma is one of the most common chronic diseases and it is still on the rise with a prevalence estimated at 8- 9% of the U.S. population (~40 million) with an estimated cost of $50 billion/year in the US. New therapeutic approaches are needed that offer the potential for a long lasting cure, instead of merely suppressing chronic lung inflammation. Allergic asthma is the most common asthma endotype and is thought to be driven in large part by a type 2 airway immune response to inhaled allergens. Defining how memory CD4+ T helper type 2 (Th2) cells initiate an airway recall response to aeroallergens has the potential to offer new therapeutic approaches to treat allergic asthma. Recently, a new paradigm in memory T cell biology has emerged in which tissue-resident memory T cells (Trm) persisting in non-lymphoid tissue are critical for initiating antigen-specific recall responses in peripheral tissue. Trm are a unique subset of memory T cells that are anatomically positioned and transcriptionally programmed to initiate the tissue amnestic response to antigen. During periods of disease quiescence, approximately 5-10% of effector Th2 cells driving allergic asthma give rise to tissue- resident memory Th2 cells (Th2-Trm) that are retained in the lung and are thus poised to respond upon allergen re-exposure. While Th2-Trm have been described in a murine model of asthma, how they promote allergic inflammation is unclear. The objective of this proposal is to define the mechanisms whereby Th2-Trm persisting in the lung orchestrates a recall response to inhaled allergens. Our central hypothesis is that Th2- Trm ignite allergic airway inflammation via a rapid and enhanced response to cognate antigen in the airway and the ability to recruit circulating Th2 cells (Th2-Tcr) to the sites of antigen presentation in the lung. Mechanistically, we hypothesize that Th2-Trm co-localize with DCs expressing the Th2 cell-attracting chemokine CCL17 and after allergen re-challenge rapidly produce type 2 cytokines that initiate allergic inflammation and markedly enhance DC expression of CCL17. This increased CCL17 expression recruits Th2- Tcr cells from the blood to sites of antigen presentation where Th2-Tcr receive a ?second touch? from cognate antigen loaded and activated DCs and become fully competent to amplify allergic inflammation. We propose to use innovative experimental systems to define the function of Th2-Trm, including parabiosis, a novel CCR4 ligand ?CCL17 and CCL22? dual reporter mouse, and single cell RNA-seq analysis of murine lung and human airway mucosal CD4+ T cells obtained via bronchial brushing. Specifically, we propose: (1) To define the function of lung-resident Th2-Trm in regulating recurrent allergic airway inflammation in murine models and to define the transcriptional phenotype of murine and human lung Th2-Trm and Th2-Tcr; and (2) To define the role of CCL17 in regulating Th2-Trm and Th2-Tcr cell localization and function and to define the functional properties of CCL17-expressing lung DCs in promoting asthma. Defining the mechanisms regulating Th2-Trm function in the asthmatic airway has the potential to yield new therapeutic approaches for allergic asthma.
Memory CD4+ T helper type 2 (Th2) cells are critical in promoting allergic asthma, the most common asthma endotype. This application proposes to define the function of newly described lung-resident memory Th2 cells in driving recurrent allergic airway inflammation. The successful completion of the proposed studies has the potential to focus new asthma therapies on specifically targeting the biology of lung-resident memory Th2 cells.
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