2023
Proc Natl Acad Sci U S A. 2023 Oct 3;120(40):e2306761120. doi: 10.1073/pnas.2306761120. Epub 2023 Sep 27.
Divergent roles for STAT4 in shaping differentiation of cytotoxic ILC1 and NK cells during gut inflammation
Department of Molecular Medicine, Sapienza University of Rome, Rome 00161, Italy. Laboratory affiliated to Istituto Pasteur Italia-Fondazione Cenci Bolognetti, Rome 00161, Italy. Laboratory of Innate Immunity, Institute of Microbiology, Infectious Diseases and Immunology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Campus Benjamin Franklin, Berlin 12203, Germany. Mucosal and Developmental Immunology, Deutsches Rheuma-Forschungszentrum, an Institute of the Leibniz Association, Berlin 10117, Germany. Center for Life Nano- & Neuro-Science, Istituto Italiano di Tecnologia, Rome 00161, Italy. Biodata Mining and Discovery Section, Office of Science and Technology, National Institute of Arthritis, Musculoskeletal and Skin Diseases, NIH, Bethesda, MD 20892. Translational Immunology Section, Office of Science and Technology, National Institute of Arthritis, Musculoskeletal and Skin Diseases, NIH, Bethesda, MD 20892. Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo 1608582, Japan. Istituti di Ricovero e Cura a Carattere Scientifico Neuromed, Isernia 86077, Italy. Innate Immunity Unit, Institut Pasteur, Université Paris Cité, INSERM U1223, Paris 75724, France.
Service type: Knockout mice
Abstract
Natural killer (NK) cells and type 1 innate lymphoid cells (ILC1) require signal transducer and activator of transcription 4 (STAT4) to elicit rapid effector responses and protect against pathogens. By combining genetic and transcriptomic approaches, we uncovered divergent roles for STAT4 in regulating effector differentiation of these functionally related cell types. Stat4 deletion in Ncr1-expressing cells led to impaired NK cell terminal differentiation as well as to an unexpected increased generation of cytotoxic ILC1 during intestinal inflammation. Mechanistically, Stat4-deficient ILC1 exhibited upregulation of gene modules regulated by STAT5 in vivo and an aberrant effector differentiation upon in vitro stimulation with IL-2, used as a prototypical STAT5 activator. Moreover, STAT4 expression in NCR+ innate lymphocytes restrained gut inflammation in the dextran sulfate sodium-induced colitis model limiting pathogenic production of IL-13 from adaptive CD4+ T cells in the large intestine. Collectively, our data shed light on shared and distinctive mechanisms of STAT4-regulated transcriptional control in NK cells and ILC1 required for intestinal inflammatory responses.
Keywords: JAK/STAT; NK cells; inflammation; innate lymphocytes; transcriptional regulations.
