Roles of group 2 innate lymphoid cells in type 2 immunity and asthma

The National Institute of Allergy and Infectious Diseases awarded Mayo Clinic Arizona $638,403 on August 18, 2026, under the Allergy and Infectious Diseases Research program (CFDA 93.855) to investigate the roles of group 2 innate lymphoid cells (ILC2s) in type 2 immunity and asthma.

The project examines immunological mechanisms underlying airway inflammation in asthma patients, focusing on how ILC2s—which rapidly produce type 2 cytokines—regulate adaptive immune responses in the lungs and airways. Preliminary studies using mouse models of allergen-induced type 2 immunity showed that ILC2s appear to function as master regulators that either promote or suppress adaptive type 2 immune responses depending on exposure context. Aim 1 will define the roles of lung ILC2s and ILC2-derived GM-CSF in developing allergen-specific immune memory and tissue-resident memory T cells using ILC2-deficient mice. Aim 2 will determine the regulatory roles of lung ILC2s in chronic allergen-induced airway inflammation, characterize ILC2 heterogeneity during chronic inflammation, and examine the regulatory roles of ILC2-derived IL-10 using conditional knockout mice.

The performance period runs through July 31, 2027, with work performed in Scottsdale, Arizona. This is a Project Grant, classified as assistance funding to a public or nonprofit institution for biomedical research.

Abstract

This project's long-term goal is to understand immunological mechanisms of type 2 immunity and asthma. 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. However, several overarching questions remain regarding the role of ILC2S in asthma: how are ILC2S involved in the type 2 immune system in the lungs and airways? Do ILC2S work in concert with other immune cells such as CD4+ t cells, and if so, how? In preliminary studies, we began to address these questions using mouse models of allergen-induced type 2 immunity in the lungs. When naïve animals were acutely exposed to a natural airborne allergen, allergen- specific TH2-type CD4+ t cells were markedly reduced in ILC2-deficient mice compared with control mice. Paradoxically, when naïve animals were repeatedly exposed to the same allergen, ILC2-deficient mice showed markedly increased levels of type 2 cytokines and airway eosinophils compared with control mice. Therefore, we hypothesize that lung ILC2S serve as a master regulator in the airways by promoting or suppressing adaptive type 2 immune responses, depending on the context. In aim 1, we will define the roles of lung ILC2S in developing allergen-specific immune memory during acute allergen exposure. We will examine the roles of ILC2S and ILC2-derived GM-CSF in promoting antigen- specific tissue-resident memory t cells by using ILC2-deficient rorafl/FLIL7RA-CRE mice. In aim 2, we will determine the regulatory roles of lung ILC2S in allergen-induced chronic airway inflammation. We will characterize heterogeneity of ILC2S during chronic airway inflammation. The regulatory roles of ILC2-derived IL-10 will be examined by conditional knockout mice and adoptive transfer model. In aim 3, we will elucidate the regulatory roles of lung ILC2S in type 2 immunity in the animals with experienced immunity mimicking adult humans. By using a newly developed mouse model that allows natural exposure of laboratory mice to various microbes, we will investigate the immunophenotypes and gene expression of ILC2S in immune experienced hosts at steady-state and during chronic inflammation. The regulatory functions of ILC2S from immune experienced hosts will be examined by in vivo approaches. The potential impact of these studies is that they will reveal how type 2 immune responses in the airways are initiated, sustained, and controlled-and how ILC2S are uniquely involved in each of these stages. Our studies will also generate new knowledge regarding how the immunologic functions of lung ILC2S from immune-experienced hosts differ from those from conventional pathogen-free hosts, linking mouse models and a human system. These studies will enhance our understanding of the pathophysiology of asthma and related airway diseases and support the translation of findings from mouse models to human biology.