Type 2 Innate Lymphoid Cell Dynamics in Allergic Airway Inflammation

Type 2 innate lymphoid cells (ILC2s) are a specialised subset of tissue-resident lymphocytes that rapidly produce interleukins IL-5, IL-9 and IL-13 in response to epithelial‐derived signals. In allergic airway inflammation, these cells integrate alarmin cues—such as IL-33, thymic stromal lymphopoietin and TL1A—with local metabolic and adhesive signals to orchestrate eosinophil recruitment, mucus hypersecretion and airway hyperreactivity. Beyond cytokine production, ILC2s regulate the migration of dendritic cells and other effector populations by secreting factors that modulate lymphatic endothelial function. Their activity is tightly controlled by inhibitory receptors and autocrine feedback loops to prevent excessive tissue injury, yet remains sufficiently plastic to adapt to viral or parasitic challenge. Emerging evidence highlights the dual role of ILC2s in both initiating local type 2 pathology and in directing systemic immunity through lymph node homing.

Research from Nature Portfolio

Recent studies have revealed that ILC2-derived leukaemia inhibitory factor (LIF) is indispensable for immune egress from the lung under both allergic and viral challenge. Loss of LIF production by ILC2s impairs the induction of pulmonary lymphatic chemokines, notably CCL21, leading to retention of dendritic cells and plasmacytoid populations in the lung and defective lymph node priming. Separately, work on the programmed cell death protein-1 (PD-1) axis has shown that PD-1 functions as a metabolic checkpoint in ILC2s. Engagement of PD-1 limits glycolytic and glutaminolytic flux, restrains proliferation and reduces type 2 cytokine output, while PD-1 agonism in a humanised model alleviates airway hyperreactivity and lung inflammation, underscoring the therapeutic promise of inhibitory receptor modulation.

Type 2 Innate Lymphoid Cell Dynamics in Allergic Airway Inflammation publication trend

The graph below shows the total number of articles in type 2 innate lymphoid cell dynamics in allergic airway inflammation across all publications each year (not limited to Nature Index journals).

Technical terms

Type 2 innate lymphoid cell (ILC2): Tissue‐resident lymphocyte subset producing IL-5, IL-9 and IL-13 to drive type 2 inflammation.

Alarmin: Epithelial‐derived cytokine released upon tissue damage (e.g., IL-33, TL1A) that activates ILC2s.

Leukaemia inhibitory factor (LIF): Cytokine secreted by ILC2s that induces lymphatic endothelial CCL21 production and immune cell egress.

PD-1: Inhibitory receptor on ILC2s that regulates metabolic activity and cytokine output.

SIRPα–CD47 axis: Cell‐surface inhibitory pathway that suppresses ILC2 activation and effector metabolism.

TL1A: Tumour necrosis factor superfamily ligand acting as an alarmin to enhance ILC2-derived IL-9 and promote airway inflammation.

References

1. ILC2-derived LIF licences progress from tissue to systemic immunity. Nature (2024).
2. SIRPα engagement regulates ILC2 effector function and alleviates airway hyperreactivity via modulating energy metabolism. Cellular & Molecular Immunology (2024).
3. TL1A is an epithelial alarmin that cooperates with IL-33 for initiation of allergic airway inflammation. Journal of Experimental Medicine (2024).
4. PD-1 pathway regulates ILC2 metabolism and PD-1 agonist treatment ameliorates airway hyperreactivity. Nature Communications (2020).