c-Maf restrains T-bet-driven programming of CCR6-negative group 3 innate lymphoid cells

RORgt+ group 3 innate lymphoid cells (ILC3s) maintain intestinal homeostasis through secretion of type 3 cytokines such as interleukin (IL)-17 and IL-22. However, CCR6- ILC3s additionally co-express T-bet allowing for the acquisition of type 1 effector functions. While T-bet controls the type 1 programming of ILC3s, the molecular mechanisms governing T-bet are undefined. Here, we identify c-Maf as a crucial negative regulator of murine T-bet+ CCR6- ILC3s. Phenotypic and transcriptomic profiling of c-Maf-deficient CCR6- ILC3s revealed a hyper type 1 differentiation status, characterized by overexpression of ILC1/NK cell-related genes and downregulation of type 3 signature genes. On the molecular level, c-Maf directly restrained T-bet expression. Conversely, c-Maf expression was dependent on T-bet and regulated by IL-1b, IL-18 and Notch signals. Thus, we define c-Maf as a crucial cell-intrinsic brake in the type 1 effector acquisition which forms a negative feedback loop with T-bet to preserve the identity of CCR6-ILC3s

Antibiotic use during pregnancy is linked to offspring gut microbial dysbiosis, barrier disruption, and altered immunity along the gut–lung axis

Antibiotic use during pregnancy is associated with increased asthma risk in children. Since approximately 25% of women use antibiotics during pregnancy, it is important to identify the pathways involved in this phenomenon. We investigate how mother-to-offspring transfer of antibiotic-induced gut microbial dysbiosis influences immune system development along the gut–lung axis. Using a mouse model of maternal antibiotic exposure during pregnancy, we immunophenotyped offspring in early life and after asthma induction. In early life, prenatal-antibiotic exposed offspring exhibited gut microbial dysbiosis, intestinal inflammation (increased fecal lipocalin-2 and IgA), and dysregulated intestinal ILC3 subtypes. Intestinal barrier dysfunction in the offspring was indicated by a FITC-dextran intestinal permeability assay and circulating lipopolysaccharide. This was accompanied by increased T-helper (Th)17 cell percentages in the offspring's blood and lungs in both early life and after allergy induction. Lung tissue additionally showed increased percentages of RORγt T-regulatory (Treg) cells at both time points. Our investigation of the gut–lung axis identifies early-life gut dysbiosis, intestinal inflammation, and barrier dysfunction as a possible developmental programming event promoting increased expression of RORγt in blood and lung CD4+ T cells that may contribute to increased asthma risk.Fil: Alhasan, Moumen M.. Universität zu Berlin; AlemaniaFil: Hölsken, Oliver. Freie Universität Berlin; AlemaniaFil: Duerr, Claudia. Freie Universität Berlin; AlemaniaFil: Helfrich, Sofia. Freie Universität Berlin; AlemaniaFil: Branzk, Nora. Freie Universität Berlin; AlemaniaFil: Philipp, Alina. Freie Universität Berlin; AlemaniaFil: Leitz, Dominik. Freie Universität Berlin; AlemaniaFil: Duerr, Julia. Freie Universität Berlin; AlemaniaFil: Almousa, Yahia. Freie Universität Berlin; AlemaniaFil: Barrientos, Gabriela Laura. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Hospital Aleman; ArgentinaFil: Mohn, William W.. University of British Columbia; CanadáFil: Gamradt, Stefanie. Freie Universität Berlin; AlemaniaFil: Conrad, Melanie L.. Freie Universität Berlin; Alemani