TY - JOUR T1 - Group 3 Innate Lymphoid Cells are regulated by WASP in a microbiota-dependent manner JF - bioRxiv DO - 10.1101/2022.07.19.500438 SP - 2022.07.19.500438 AU - Amlan Biswas AU - Naresh S Redhu AU - Anubhab Nandy AU - Yu Hui Kang AU - Michael Field AU - Ryan Kelly AU - Liza Konnikova AU - Jeremy A. Goettel AU - Amy M. Tsou AU - Bruce Horwitz AU - Scott B. Snapper Y1 - 2022/01/01 UR - http://biorxiv.org/content/early/2022/07/20/2022.07.19.500438.abstract N2 - Wiskott-Aldrich syndrome protein (WASP) is a cytoskeletal regulator that is largely restricted to hematopoietic cells. While WASP expression in both lymphocytes and macrophages play a critical role in maintaining intestinal homeostasis, the function of WASP in innate lymphoid cells is unknown. Here we analyzed the role of WASP in the differentiation and function of group 3 innate lymphoid cells (ILC3s). WASP-deficient mice (Was-/-) have a marked reduction in ILC3s. Moreover, antimicrobial peptide expression in response to ILC3-derived IL-22 was also reduced in the absence of WASP. In Was-/- mice, we observed a reduction in CCR6+ ILC3s, cells known to restrict immune responses to commensal bacteria. WASP-deficient mice were more susceptible to Citrobacter rodentium, an enteric infection controlled by ILC3s. Interestingly, there was no reduction in ILC3s in Was-/- germ-free mice when compared to WT germ-free mice. ILC3s lacking WASP expression also demonstrated microbially-dependent alterations in gene expression associated with cell migration. Finally, ILC3-like (Rorgt+CD3-) cells were reduced in the GI tract of WASP-deficient patients. In conclusion, ILC3-specific expression of WASP is critical for the generation and function of ILC3s in the presence of commensal microflora. Aberrant ILC3 function in the setting of WASP-deficiency may contribute to underlying disease pathogenesis.Competing Interest StatementS.B.S. is supported by grants or in-kind contributions from Pfizer, Novartis, Takeda, and Regeneron. He is on the scientific advisory boards of Pfizer, Janssen, IFM Therapeutics, Merck, Lycera, Inc., Celgene, Lilly, Pandion Therapeutics, and Applied Molecular Transport. He has consulted for Amgen, Hoffman La-Roche. ER -