STING Gain-of-Function Disrupts Lymph Node Organogenesis and Innate Lymphoid Cell Development in Mice
Brock G. Bennion,
Carys A. Croft,
Teresa L. Ai,
Wei Qian,
Amber M. Menos,
Cathrine A. Miner,
Marie-Louis Frémond,
Jean-Marc Doisne,
Prabhakar S. Andhey,
Derek J. Platt,
Jennifer K. Bando,
Erin R. Wang,
Hella Luksch,
Thierry J. Molina,
Elisha D.O. Roberson,
Maxim N. Artyomov,
Angela Rösen-Wolff,
Marco Colonna,
Frédéric Rieux-Laucat,
James P. Di Santo,
Bénédicte Neven,
Jonathan J. Miner
Affiliations
Brock G. Bennion
Department of Pathology and Immunology, Washington University School of Medicine, Saint Louis, MO 63110, USA
Carys A. Croft
Innate Immunity Unit, Institut Pasteur, Paris, France; INSERM U1223, Institut Pasteur, Paris, France; Université de Paris, Sorbonne Paris Cité, Paris, France
Teresa L. Ai
Department of Medicine, Washington University School of Medicine, Saint Louis, MO 63110, USA
Wei Qian
Department of Medicine, Washington University School of Medicine, Saint Louis, MO 63110, USA
Amber M. Menos
Department of Medicine, Washington University School of Medicine, Saint Louis, MO 63110, USA
Cathrine A. Miner
Department of Medicine, Washington University School of Medicine, Saint Louis, MO 63110, USA
Marie-Louis Frémond
Department of Hematology and Rheumatology, Necker-Enfants Malades Hospital, APHP, Paris, France
Jean-Marc Doisne
Innate Immunity Unit, Institut Pasteur, Paris, France; INSERM U1223, Institut Pasteur, Paris, France
Prabhakar S. Andhey
Department of Pathology and Immunology, Washington University School of Medicine, Saint Louis, MO 63110, USA
Derek J. Platt
Department of Molecular Microbiology, Washington University School of Medicine, Saint Louis, MO 63110, USA
Jennifer K. Bando
Department of Pathology and Immunology, Washington University School of Medicine, Saint Louis, MO 63110, USA
Erin R. Wang
Department of Medicine, Washington University School of Medicine, Saint Louis, MO 63110, USA
Hella Luksch
Department of Pediatrics, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
Thierry J. Molina
Université de Paris, Department of Pathology, Necker-Enfants Malades Hospital, Paris, France
Elisha D.O. Roberson
Department of Medicine, Washington University School of Medicine, Saint Louis, MO 63110, USA; Department of Genetics, Washington University School of Medicine, Saint Louis, MO 63110, USA
Maxim N. Artyomov
Department of Pathology and Immunology, Washington University School of Medicine, Saint Louis, MO 63110, USA
Angela Rösen-Wolff
Department of Pediatrics, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
Marco Colonna
Department of Pathology and Immunology, Washington University School of Medicine, Saint Louis, MO 63110, USA
Frédéric Rieux-Laucat
Université de Paris, Institut Imagine, Laboratory of Immunogenetics of Pediatric Autoimmune Diseases, INSERM UMR 1163, 75015 Paris, France
James P. Di Santo
Innate Immunity Unit, Institut Pasteur, Paris, France; INSERM U1223, Institut Pasteur, Paris, France
Bénédicte Neven
Department of Hematology and Rheumatology, Necker-Enfants Malades Hospital, APHP, Paris, France; Université de Paris, Institut Imagine, Laboratory of Immunogenetics of Pediatric Autoimmune Diseases, INSERM UMR 1163, 75015 Paris, France; Corresponding author
Jonathan J. Miner
Department of Pathology and Immunology, Washington University School of Medicine, Saint Louis, MO 63110, USA; Department of Medicine, Washington University School of Medicine, Saint Louis, MO 63110, USA; Department of Molecular Microbiology, Washington University School of Medicine, Saint Louis, MO 63110, USA; Corresponding author
Summary: STING gain-of-function causes autoimmunity and immunodeficiency in mice and STING-associated vasculopathy with onset in infancy (SAVI) in humans. Here, we report that STING gain-of-function in mice prevents development of lymph nodes and Peyer’s patches. We show that the absence of secondary lymphoid organs is associated with diminished numbers of innate lymphoid cells (ILCs), including lymphoid tissue inducer (LTi) cells. Although wild-type (WT) α4β7+ progenitors differentiate efficiently into LTi cells, STING gain-of-function progenitors do not. Furthermore, STING gain-of-function impairs development of all types of ILCs. Patients with STING gain-of-function mutations have fewer ILCs, although they still have lymph nodes. In mice, expression of the STING mutant in RORγT-positive lineages prevents development of lymph nodes and reduces numbers of LTi cells. RORγT lineage-specific expression of STING gain-of-function also causes lung disease. Since RORγT is expressed exclusively in LTi cells during fetal development, our findings suggest that STING gain-of-function prevents lymph node organogenesis by reducing LTi cell numbers in mice.
