Immune regulation by group 2 innate lymphoid cells following upper respiratory viral infections

Abstract

Innate lymphoid cells (ILCs) are a group of innate immune cells that lack antigen-specific receptors and respond rapidly to nonspecific stimuli by producing cytokines. Recently, their role in immune regulation has attracted increasing attention. Among them, group 2 ILCs (ILC2s) are activated by epithelial-derived alarmins, such as IL-33, IL-25, and TSLP, and produce type 2 cytokines including IL-5, IL-13, and IL-9. These cytokines contribute to eosinophil recruitment, enhanced mucus secretion, and airway hyper-responsiveness, playing key roles in the initiation and amplification of allergic inflammation.

ILC2s are predominantly localized in the mucosal barrier tissues, including the lungs, gastrointestinal tract, skin, and upper respiratory tract. Notably, their presence has been confirmed in the tonsils and adenoids. However, infants may exhibit a higher proportion of ILC2s than adults, which has been implicated in susceptibility to asthma-like symptoms and allergic diseases following respiratory syncytial virus (RSV) infection. An increase in nasal ILC2s has been observed in infants following RSV infection, suggesting that sustained ILC2 activation contributes to persistent type 2 inflammation and asthma risk.

ILC2s are involved in the pathogenesis of various allergic diseases, including bronchial asthma, allergic rhinitis, eosinophilic chronic rhinosinusitis, and atopic dermatitis. Their abundance is associated with disease severity and resistance to treatment. ILC2s may also exhibit resistance to corticosteroid suppression, a key drug in allergy treatment, thereby highlighting their involvement in the pathology of steroid-refractory asthma. Moreover, novel regulatory mechanisms involving the TNF superfamily (such as RANKL and TL1A) and neurometabolic factors (including prostaglandin D2, noradrenaline, and leptin) have emerged, indicating the role of neuroimmune crosstalk in allergic inflammation.

Recent efforts have focused on developing targeted therapies that modulate the ILC2 activation pathways. Biologics targeting IL-5, IL-13, and IL-4Rα, as well as upstream alarmins such as IL-33, TSLP, and IL-25, are already in clinical use or under investigation. Because ILC2s also bridge innate and adaptive immunity, their roles in infection, vaccine responses, and tumor immunity have been explored. Thus, ILC2s are increasingly being recognized as promising therapeutic targets for future immune-related disease interventions.