J Exp Med (2024) 221 (6): e20231236.
Abstract:
![](https://cdn.rupress.org/rup/content_public/journal/jem/221/6/10.1084_jem.20231236/1/m_jem_20231236_ga.png?Expires=1715955673&Signature=SsOxmu6l8FzPczH3PXFCVdmiAyg3QTJu5NOZ0HOkZLUH~EH-tPhS078sBnhaubff4iAtkMivE6zw9SI4TLQIQ9Cwo3jipk-trYJy4lICHsY5jmnsrgo-BpDvSt7-wNdznzGTXWe18AlXPB-exMW2dx1yqTXgmVZ1Tr73QaPUr3oJf97pK8Bm7O0shdCkjZJ7WDiMndUPJ18-e61gH3uF1Wvu2jIzGHncCZDADpyfsDiK3PT3oyBo1vnfPOQva~r5m6oCP5tll70B3eHWZybuudkfb3Ve51dfuQRmoZYC5YWu3N4zim--HIinGRpOyLboUN9ulecqqKddd3TBgEz1RA__&Key-Pair-Id=APKAIE5G5CRDK6RD3PGA)
Epithelium-derived cytokines or alarmins, such as interleukin-33 (IL-33) and thymic stromal lymphopoietin (TSLP), are major players in type 2 immunity and asthma. Here, we demonstrate that TNF-like ligand 1A (TL1A) is an epithelial alarmin, constitutively expressed in alveolar epithelium at steady state in both mice and humans, which cooperates with IL-33 for early induction of IL-9high ILC2s during the initiation of allergic airway inflammation. Upon synergistic activation by IL-33 and TL1A, lung ILC2s acquire a transient IL-9highGATA3low “ILC9” phenotype and produce prodigious amounts of IL-9. A combination of large-scale proteomic analyses, lung intravital microscopy, and adoptive transfer of ILC9 cells revealed that high IL-9 expression distinguishes a multicytokine-producing state-of-activated ILC2s with an increased capacity to initiate IL-5-dependent allergic airway inflammation. Similar to IL-33 and TSLP, TL1A is expressed in airway basal cells in healthy and asthmatic human lungs. Together, these results indicate that TL1A is an epithelium-derived cytokine and an important cofactor of IL-33 in the airways.