The context-dependent role of group 2 innate lymphoid cells in lung diseases

Abstract

Group 2 innate lymphoid cells (ILC2s), a subset of innate lymphoid cells (ILCs) lacking antigen-specific receptors and functionally mirroring T helper 2 (Th2) cells, are indispensable components of the innate immune system that lack antigen-specific receptors but phenotypically and functionally mirror T helper 2 (Th2) cells, particularly in their expression of the transcription factor GATA3 and the secretion of type 2 cytokines for mediating type 2 immune responses. ILC2s are tissue-resident cells in mucosal tissues, including the lung, where they play crucial roles in maintaining tissue homeostasis and regulating immune responses. ILC2s are poised to respond to environmental signals such as IL-25, IL-33, and TSLP, which activate and expand ILC2s. Their functions are highly context-dependent and influenced by interactions with other immune cells. In this review, we summarize recent findings on the roles of ILC2s in lung diseases, highlighting their typical characteristics and their responsiveness to environmental signals in the context of pulmonary pathology. We also discuss potential therapeutic strategies targeting ILC2s, which may offer new avenues for the treatment of inflammatory lung diseases. Understanding the mechanisms by which ILC2s contribute to lung disease progression will provide valuable insights for the development of novel diagnostic (e.g., ILC2 phenotypic markers) and therapeutic approaches (e.g., targeting ILC2 plasticity or alarmin-ILC2 signaling axes).

1. Introduction

Group 2 innate lymphoid cells (ILC2s) are tissue-resident innate lymphocytes characterized by the absence of antigen-specific receptors (e.g., TCR/BCR) and the expression of lineage markers such as CRTH2, ST2 (IL-33 receptor), and GATA3 (master transcription factor). Developmentally, ILC2s originate from common lymphoid progenitors (CLPs) in the bone marrow, where they differentiate into ILC2 progenitors (ILC2Ps) under the regulation of transcription factors, including GATA3 and RORα. ILC2s in most tissues are established during the perinatal period. In adulthood, ILC2s in the lungs, small intestine, and fat are replaced less frequently by circulating ILC2s and are maintained more through self-renewal. ILC2s in the bone marrow and skin are replaced more quickly by de novo ILC2s [1]. However, under conditions of parasitic, fungal, or allergen infection, circulating ILC2s of small intestine and bone marrow origin are recruited to the lungs [2–4]. In the lungs, tissue-resident ILC2s preferentially accumulate in areas surrounding larger airways and blood vessels [5,6]. Functionally, ILC2s respond to epithelial-derived alarmins (IL-25, IL-33, and TSLP) to secrete type 2 cytokines (IL-4, IL-5, and IL-13) and tissue repair factors (Amphiregulin and Areg). Additionally, ILC2s interact with other immune cells (e.g., Th2 cells, eosinophils) and neuroendocrine signals (e.g., dopamine, NMU) to regulate immune homeostasis and inflammation.

Under physiological conditions, ILC2s contribute to tissue repair and host defense, particularly against helminth infections, through amphiregulin production [7,8]. However, dysregulated ILC2 activation contributes to pathological inflammation in certain diseases. In asthma [9], it induces airway hyperresponsiveness (AHR), whereas in pulmonary fibrosis [10,11], it exacerbates collagen deposition and disease progression.

Despite the growing interest in ILC2s, existing reviews often focus on their development or their roles in a specific disease. The complex roles of ILC2s in various lung diseases have not been comprehensively compared and discussed. In this review, we aim to summarize the current advances in understanding the role of ILC2s in various lung diseases, including asthma, chronic obstructive pulmonary disease (COPD), pulmonary fibrosis, lung infections (helminths, viruses, bacteria, protozoans), acute lung injury and lung cancer. This review also provides an improved understanding of the mechanisms that regulate ILC2 functions and their interactions with other immune cells and tissues in different lung diseases (Figure 1). Understanding the versatile role of lung ILC2s is crucial for developing effective therapeutic strategies for lung diseases.