Wednesday, April 2, 2025
4/2/2025
Roles of Group 2 Innate Lymphoid Cells in Asthma - PROJECT SUMMARY/ABSTRACT This project’s long-term goal is to understand immunological mechanisms of asthma and type 2 immunity. Airway inflammation in patients with asthma is generally characterized by increased lymphocytes producing type 2 cytokines. Group 2 innate lymphoid cells (ILC2s) that rapidly produce large quantities of type 2 cytokines have been implicated in the innate arm of type 2 immunity and pathophysiology of allergic diseases. However, several major questions remain: How are ILC2s involved in promoting or regulating type 2 airway inflammation? Do ILC2s work in concert with other immune cells, such as CD4+ T cells? If so, how? And, importantly, do ILC2s in a mature immune/microbial environment, like the adult human body, behave similarly to those in laboratory mice that are housed in a clean environment? The objective of this application is to address these gaps in our knowledge. To achieve the goal of this project, we began to directly analyze the roles of ILC2s by deleting them using a genetic approach in mice. When naïve animals were acutely exposed to a natural airborne allergen, the Th2- type memory responses were markedly reduced in ILC2-deficient mice. Paradoxically, when naïve animals were exposed repeatedly to the same allergen, ILC2-deficient mice showed a marked increase in their levels of type 2 cytokines and eosinophilic airway inflammation. Therefore, we hypothesize that lung ILC2s serve as a master regulator in the airways by promoting and suppressing adaptive type 2 immune responses, depending on the context. In Aim 1, we will define the roles of lung ILC2s in the development of immune memory during acute allergen exposure. We will investigate how ILC2s promote antigen-specific Th2-type tissue-resident memory T cells. In Aim 2, we will determine the regulatory roles of lung ILC2s in allergen-induced chronic airway inflammation. We will investigate how lung ILC2s in concert with regulatory CD4+ T cells suppress excessive immune responses and inflammation. In Aim 3, we will elucidate the roles of lung ILC2s in mice with physiologic microbial exposure. We will leverage a novel “dirty mice” model and characterize the functions of ILC2s in mice that have been exposed naturally to pathogens and microbes, similarly to humans. We will integrate several mouse models to investigate the cause-effect relationships between ILC2s and type 2 immunity in the airways. The tools, technical expertise, and resource necessary to accomplish this project are in place. Successful completion of this proposal will help to explain how type 2 immune responses develop, persist, and are regulated in the airways and how ILC2s contribute to these processes. Ultimately, these studies will clarify the immunological mechanisms and pathophysiology of asthma and related airway disorders, allowing for development of novel strategies for the diagnosis and treatment for the diseases.
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