Imprinting of nasal Th2 cell trafficking during allergic sensitization

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 DESCRIPTION (provided by applicant): Allergic rhinitis is a chronic inflammatory disease of the upper airways that affects approximately 60million people in the United States and is associated with significant socioeconomic costs. Disease is caused by atopic sensitization to aeroallergens in the nasal passages resulting in IgE-mediated clinical signs. Allergic responses are driven by CD4+ Th2 cells and the transfer of these cells is sufficient to induce disease. The induction and recruitment of allergen-specific Th2 cells to the nasal mucosa could have a significant impact on promoting rhinitis, yet little is known regarding the regulation or homing requirements of these cells. We hypothesize that Th2 cell migration to the nasal mucosa is governed by the expression of specific trafficking receptors that are imprinted by nasal dendritic cells. Due to its location, the nasal-associated lymphoid tissue likely plays a crucial role, which remains to be fully elucidated. We will use mouse models and human clinical tissues to identify the nasal trafficking profile and the mechanisms that regulate it. We will define the chemokine receptor requirements for Th2 cell homing to and motility within the nasal mucosa in response to local allergen sensitization in mice. Findings will be corroborated by ex vivo phenotypic studies in human nasal tissues from controls or subjects with chronic rhinosinusitis. The mechanistic events that underlie the imprinting will focus on the role of tissue dendritic cells. Understanding the molecular mechanisms of the cellular trafficking requirements of the nasal mucosa is of direct clinical importance and will inform on new avenues for the treatment of allergic diseases. Our eventual goal is to exploit our mechanistic insights to modulate the tissue-tropic trafficking profiles induced in allergen-specific nasal CD4+ T cells to interfere with their migration and curtail the cyclic nature of recurrent Th2-driven rhinitis.