Mechanisms of Allergen-induced Type 2 Immunity

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The long-term objective of this grant is to investigate how airway exposure to natural allergens leads to development of type 2 immunity and allergic diseases. Exaggerated type 2 immune responses are implicated in a wide variety of disorders ranging from asthma to food allergy. Traditionally, CD4+ type 2 helper T (Th2) cells that produce interleukin (IL)-4, IL-5, and IL-13 have been considered major players in directing the pathophysiology of these diseases, such as airway eosinophilia and IgE antibody production. During the previous funding period of this MERIT Award, we have made major progress in all three Aims. We found that allergen- specific T follicular helper (Tfh) cells and tissue-resident memory (Trm) cells play distinct roles in allergic immune responses. Specifically, Tfh cells promoted production of allergen-specific IgE antibodies and development of acute anaphylaxis while Th2-type Trm cells likely play a role in allergen-induce type 2 cytokine production and eosinophilic inflammation in mucosal tissues. Here we request a 5-year extension of the MERIT Award to continue studying the immunologic mechanism of type 2 immunity. We will finalize and submit at least 4 manuscripts that are described in the progress report. We will extend the studies of the previous funding period and define how allergen exposure mediates various immunologic and clinical phenotypes of allergic diseases. In Aim 1, we will examine the the roles of Th2-type Trm cells in mediating type 2 cytokine production and eosinophilic inflammation in airway mucosa. We will leverage mouse models and use parabiosis and immunologic and genetic approaches to critically define the functions of Trm cells and their regulatory mechanisms. In Aim 2, we will examine how lung T resident helper (Trh) cells mediate IgE antibody production and inflammation in mucosal tissues. Our preliminarily data show the presence of CD4+PD-1+FR4+ Trh cells, a new subset of Tfh-like cells, in the lungs of mice exposed to allergens. We will use mouse genetic approaches to characterize this new cell type and understand its roles in type 2 immunity. In Aim 3, we continue collaborating with Dr. Shiv Kale, and ask a fundamental question why certain allergens robustly induce type 2 immunity. We will take a fungal functional genomic approach and study the roles of - galactosidases produced by fungus Alternaria. Together, the studies in these aims will define the central mechanisms underlying the development and regulation of type 2 immunity to airborne allergens and will provide an immunologic explanation regarding various clinical phenotypes of allergic diseases. Ultimately, these studies will characterize key cellular pathway(s) and molecule(s) involved in allergic immune responses, allowing identification of critical targets for development of novel therapeutic strategies to treat or to prevent asthma and allergic diseases. RELEVANCE (See instructions): Patients with asthma and allergic diseases have persistent respiratory health problems and exaggerated immune responses to common inhaled allergens. This project will investigate how exposure to natural allergens causes, prolongs, and intensifies these diseases.