Antibody Fc-receptor common gamma chain FcεR1γ stabilizes cell surface receptors in group 3 innate lymphoid cells and promotes anti-infection immunity

Group 3 innate lymphoid cells (ILC3s) are crucial for maintaining mucosal homeostasis and regulating inflammatory diseases, but the molecular mechanisms governing their phenotype and function are not fully understood. Here, we showed that ILC3s highly expressed Fcer1g gene, which encodes the antibody Fc-receptor common gamma chain (FcεR1γ). Genetic perturbation of FcεR1γ led to the absence of critical cell membrane receptors NKp46 and CD16 in ILC3s. Alanine scanning mutagenesis identified two residues in FcεR1γ that stabilize its binding partners. FcεR1γ expression in ILC3s was essential for effective protective immunity against bacterial and fungal infections. Mechanistically, FcεR1γ influenced the transcriptional state and proinflammatory cytokine production of ILC3s, relying on the CD16-FcεR1γ signaling pathway. Overall, our findings highlight the significance of FcεR1γ as an adaptor protein that stabilizes cell membrane partners in ILC3s and promotes anti-infection immunity. For bulk RNA-seq experiments, CCR6+ ILC3s were flow-sorted from the lamina propria (LPs) of Rorc-cre+Fcer1g f/f (CKO) mice and Fcer1g f/f (control) mice on day 5 after the intravenously (i.v.) injection of Candida albicans (C.A.) or vehicle (PBS). Freshly sorted CCR6+ ILC3s from each group were then lysed for library construction using SMART-Seq2 prptocol. For the single cell (sc)RNA-seq experiment, immune cells were isolated from the small intestinal lamina propria (siLPs) and colonic lamina propria (cLPs) of control and CKO mice at steady state, labeled with hashtag and fluorescent antibodies prior to fluorescence-activated cell sorting (FACS). Then the flow-sorted cells were pooled for gene expression library and Feature Barcode library construction via using Chromium Next GEM Single Cell 3ʹ Reagent Kits v3.1 (10×Genomics).