Paxbp1 plays a vital role in ILC2 homeostasis and activation through the regulation of pre-mRNA splicing 9091

Description Group 2 innate lymphoid cells (ILC2s) reside in peripheral organs and provide a first line of defense against microbial insults but also cause allergic disorders. We sought to identify a novel regulator of ILC2s by cross-referencing the single-cell transcriptome of lymphocytes recovered from the mice infected with N. brasiliensis. We found that Paxbp1 (PAX3 and PAX7 Binding Protein 1), a poorly understood nuclear protein, was highly expressed in ILC2s. To study the role in ILC2s, we deleted Paxbp1 by interbreeding Paxbp1-floxed mice to Nmur1Cre mice (Paxbp1ΔILC2), which targets ILC2s but not other lymphocytes. Paxbp1ΔILC2 mice showed a normal development of ILC2 precursors in the bone marrow whereas significant reduction of mature lung ILC2s was observed. Activation and expansion of lung ILC2s upon intranasal administration of IL-33 were dramatically impaired in KO mice. Cut&Tag revealed that Paxbp1 bound to the promoters of genes involved in cellular metabolism regulating PoI-II RNA transcription, RNA splicing, translation and cell cycle. Strikingly, mass spectrometry analysis revealed that Paxbp1 bound to TFIP11 and DHX15, components of the spliceosome. Accordingly, acute deletion of Paxbp1 by using the tamoxifen-inducible Cre recombinase resulted in impaired mRNA maturation and gene expression. Altogether, our data suggest that Paxbp1 may be a previously unrecognized player in RNA metabolism that is vital for cell survival, proliferation and activation of ILC2s. Funding Sources Supported by the Intramural Research Programs of NIAMS (grant no. ZIA AR041159 to J.J.O’S.)