Retinoic acid−related orphan receptor a is required for generation of Th2 cells in type 2 pulmonary inflammation

The transcription factor retinoic acid−related orphan receptor a (RORa) is important in regulating several physiological functions, such as cellular development, circadian rhythm, metabolism, and immunity. In two in vivo animal models of type 2 lung inflammation, Nippostrongylus brasiliensis infection and house dust mite (HDM) sensitization, we show a role for Rora in Th2 cellular development during pulmonary inflammation. N. brasiliensis infection and HDM challenge induced an increase in frequency of Rora-expressing GATA3⁺CD4 T cells in the lung. Using staggerer mice, which have a ubiquitous deletion of functional RORa, we generated bone marrow chimera mice, and we observed a delayed worm expulsion and reduced frequency in the expansion of Th2 cells and innate lymphoid type 2 cells (ILC2s) in the lungs after N. brasiliensis infection. ILC2-deficient mouse (Rora^fl/flIl7raCre) also had delayed worm expulsion with associated reduced frequency of Th2 cells and ILC2s in the lungs after N. brasiliensis infection. To further define the role for Rora-expressing Th2 cells, we used a CD4-specific Rora-deficient mouse (Rora^fl/flCD4Cre), with significantly reduced frequency of lung Th2 cells, but not ILC2, after N. brasiliensis infection and HDM challenge. Interestingly, despite the reduction in pulmonary Th2 cells in Rora^fl/flCD4Cre mice, this did not impact the expulsion of N. brasiliensis after primary and secondary infection, or the generation of lung inflammation after HDM challenge. This study demonstrates a role for RORa in Th2 cellular development during pulmonary inflammation that could be relevant to the range of inflammatory diseases in which RORa is implicated.