Microbiota engage a HDAC3 rheostat to shape ILC3 metabolism and function in the gut

Abstract

Abstract Group 3 innate lymphoid cells (ILC3s) respond to microbial colonization of the intestine to coordinate tissue health. This process involves interpretation of host- or microbial-derived signals that must be tightly regulated to preserve immunologic homeostasis. Here we examine a key epigenomic regulator that is responsive to microbial-derived factors, histone deacetylase 3 (HDAC3), and find that lineage-specific deletion results in reduced ILC3s and increased susceptibility to intestinal damage. In contrast, the lineage-specific deletion of an essential corepressor, NCOR1, results in elevated ILC3s and enhanced protection from intestinal damage. This indicates that HDAC3 mediates both a supportive deacetylase-independent role and a repressive deacetylase-dependent role in ILC3s. To explore genes promoted by HDAC3, we performed RNA sequencing and found that HDAC3 deficient ILC3s exhibit impaired transcription of genes involved in polyamine synthesis including the polyamine rate limiting enzyme ornithine decarboxylase 1 (ODC1) and spermine oxidase (SMOX). At steady state, ILC3s uniquely express high levels of ODC1 and SMOX compared to other lymphocytes, and transcription of these genes is influenced by IL-23 and the presence of the microbiota. Overall, this indicates that HDAC3 is a rheostat of ILC3 functionality in the intestine, with the hypothesis that HDAC3/NCOR1 limit tissue protective ILC3 responses, and NCOR1 independent HDAC3-mediated transcription of polyamine synthesis genes promotes ILC3 tissue protective responses. Supported by NIDDK National Research Service Award (NRSA) T32 Diversity Administrative Supplement (NOT-DK-21-016), R01AI143842, R01AI123368, R01AI145989, U01AI095608, R21CA249274, R01AI162936, R01CA274534 and the NIAID Mucosal Immunology Studies Team (MIST), an Investigators in the Pathogenesis of Infectious Disease Award from the Burroughs Wellcome Fund, Linda and Glenn Greenberg, the Dalton Family Foundation, and the Roberts Institute for Research in IBD. G.F.S. is a CRI Lloyd J. Old STAR.