RT Journal Article
SR Electronic
T1 Group 3 Innate Lymphoid Cells are regulated by WASP in a microbiota-dependent manner
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2022.07.19.500438
DO 10.1101/2022.07.19.500438
A1 Amlan Biswas
A1 Naresh S Redhu
A1 Anubhab Nandy
A1 Yu Hui Kang
A1 Michael Field
A1 Ryan Kelly
A1 Liza Konnikova
A1 Jeremy A. Goettel
A1 Amy M. Tsou
A1 Bruce Horwitz
A1 Scott B. Snapper
YR 2022
UL http://biorxiv.org/content/early/2022/07/20/2022.07.19.500438.abstract
AB 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.