Group 2 Innate Lymphoid Cells Utilize the IRF4-IL-9 Module to Coordinate Epithelial Cell Maintenance of Lung Homeostasis

Mohapatra A, Van Dyken SJ, Schneider C, Nussbaum JC, Liang HE, Locksley RM

Picture of the Locksley Lab

Locksley Lab, UCSF/HHMI: (left to right) Rich Locksley, Christophe Schneider, Steve Van Dyken, Alex Mohapatra, Jesse Nussbaum, Hong-Erh Liang (authors)

Group 2 innate lymphoid cells (ILC2s) in lung are among the initial cells that respond to allergen-provoking challenges, but how signals are integrated to mediate their upstream activation remains unclear.  Here, we demonstrate that the epithelial cytokines IL-33 and TSLP, both present in type 2 alveolar cells, synergistically activate lung ILC2s to produce the cytokines IL-13 and IL-5.  This synergy was genetically upstream of IRF4-dependent ILC2 production of IL-9, which was required for high-output cytokine production from ILC2s necessary to alter gene expression in lung epithelia that lead to airway alterations associated with allergic inflammation.  These findings highlight checkpoints marked by dual inputs (IL-33/TSLP) and a cell-intrinsic auto-activation loop (IRF4/IL-9) that must be surmounted before lung ILC2s become fully activated.

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