title: CD117+ Dendritic and Mast Cells Are Dependent on RasGRP4 to Function as Accessory Cells for Optimal Natural Killer Cell-Mediated Responses to Lipopolysaccharide.
abstract: Ras guanine nucleotide-releasing protein-4 (RasGRP4) is an evolutionarily conserved calcium-regulated, guanine nucleotide exchange factor and diacylglycerol/phorbol ester receptor. While an important intracellular signaling protein for CD117+ mast cells (MCs), its roles in other immune cells is less clear. In this study, we identified a subset of in vivo-differentiated splenic CD117+ dendritic cells (DCs) in wild-type (WT) C57BL/6 mice that unexpectedly contained RasGRP4 mRNA and protein. In regard to the biologic significance of these data to innate immunity, LPS-treated splenic CD117+ DCs from WT mice induced natural killer (NK) cells to produce much more interferon-γ (IFN-γ) than comparable DCs from RasGRP4-null mice. The ability of LPS-responsive MCs to cause NK cells to increase their expression of IFN-γ was also dependent on this intracellular signaling protein. The discovery that RasGRP4 is required for CD117+ MCs and DCs to optimally induce acute NK cell-dependent immune responses to LPS helps explain why this signaling protein has been conserved in evolution.
authors.affiliation: Department of Infectious Diseases, Immunology, and Sexual Health, St. George Hospital, and the St. George and Sutherland Clinical School, Faculty of Medicine, University of New South Wales, Sydney, New South Wales, Australia.|Laboratory of Hormones and Development (Ministry of Health), Metabolic Hospital and Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, TJ, China.
authors.forename: Saijun
authors.initials: S
authors.lastname: Zhou
authors.affiliation: Department of Infectious Diseases, Immunology, and Sexual Health, St. George Hospital, and the St. George and Sutherland Clinical School, Faculty of Medicine, University of New South Wales, Sydney, New South Wales, Australia.
authors.forename: Kumiko
authors.initials: K
authors.lastname: Tanaka
authors.affiliation: Dendritic Cell Research Laboratory, Immunity Vaccines and Immunisation, Burnet Institute, Prahran, Melbourne, Victoria, Australia.
authors.forename: Meredith
authors.initials: M
authors.lastname: O'Keeffe
authors.affiliation: Department of Infectious Diseases, Immunology, and Sexual Health, St. George Hospital, and the St. George and Sutherland Clinical School, Faculty of Medicine, University of New South Wales, Sydney, New South Wales, Australia.
authors.forename: Miao
authors.initials: M
authors.lastname: Qi
authors.affiliation: Department of Infectious Diseases, Immunology, and Sexual Health, St. George Hospital, and the St. George and Sutherland Clinical School, Faculty of Medicine, University of New South Wales, Sydney, New South Wales, Australia.
authors.forename: Fatima
authors.initials: F
authors.lastname: El-Assaad
authors.affiliation: Department of Infectious Diseases, Immunology, and Sexual Health, St. George Hospital, and the St. George and Sutherland Clinical School, Faculty of Medicine, University of New South Wales, Sydney, New South Wales, Australia.|Department of Cardiology, St. George Hospital, Sydney, New South Wales, Australia.
authors.forename: James C
authors.initials: JC
authors.lastname: Weaver
authors.affiliation: Department of Infectious Diseases, Immunology, and Sexual Health, St. George Hospital, and the St. George and Sutherland Clinical School, Faculty of Medicine, University of New South Wales, Sydney, New South Wales, Australia.
authors.forename: Gang
authors.initials: G
authors.lastname: Chen
authors.affiliation: Department of Infectious Diseases, Immunology, and Sexual Health, St. George Hospital, and the St. George and Sutherland Clinical School, Faculty of Medicine, University of New South Wales, Sydney, New South Wales, Australia.
authors.forename: Christopher
authors.initials: C
authors.lastname: Weatherall
authors.affiliation: Department of Infectious Diseases, Immunology, and Sexual Health, St. George Hospital, and the St. George and Sutherland Clinical School, Faculty of Medicine, University of New South Wales, Sydney, New South Wales, Australia.
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Infectious Diseases, Immunology, and Sexual Health, St. George Hospital, and the St. George and Sutherland Clinical School, Faculty of Medicine, University of New South Wales, Sydney, New South Wales, Australia.
authors.forename: Bill
authors.initials: B
authors.lastname: Giannakopoulos
authors.affiliation: Laboratory of Hormones and Development (Ministry of Health), Metabolic Hospital and Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, TJ, China.
authors.forename: Liming
authors.initials: L
authors.lastname: Chen
authors.affiliation: Laboratory of Hormones and Development (Ministry of Health), Metabolic Hospital and Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, TJ, China.
authors.forename: DeMint
authors.initials: D
authors.lastname: Yu
authors.affiliation: School of Biomedical Sciences and Pharmacy, University of Newcastle, Callaghan, New South Wales, Australia.|Division of Gastroenterology, Brigham and Women's Hospital, Boston, MA, United States of America.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Hamilton
authors.affiliation: Departament of Immunology, Biomedical Sciences Institute, University of São Paulo, São Paulo, Brazil.
authors.forename: Lislaine A
authors.initials: LA
authors.lastname: Wensing
authors.affiliation: Department of Infectious Diseases, Immunology, and Sexual Health, St. George Hospital, and the St. George and Sutherland Clinical School, Faculty of Medicine, University of New South Wales, Sydney, New South Wales, Australia.|School of Biomedical Sciences and Pharmacy, University of Newcastle, Callaghan, New South Wales, Australia.
authors.forename: Richard L
authors.initials: RL
authors.lastname: Stevens
authors.affiliation: Department of Infectious Diseases, Immunology, and Sexual Health, St. George Hospital, and the St. George and Sutherland Clinical School, Faculty of Medicine, University of New South Wales, Sydney, New South Wales, Australia.
authors.forename: Steven A
authors.initials: SA
authors.lastname: Krilis
mesh_terms: D000818:Animals; D018920:Coculture Techniques; D003713:Dendritic Cells / Q000276:immunology*; D007371:Interferon-gamma / Q000378:metabolism; D007694:Killer Cells, Natural / Q000276:immunology*; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008407:Mast Cells / Q000276:immunology*; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D053278:OX40 Ligand; D019009:Proto-Oncogene Proteins c-kit / Q000276:immunology*; D015398:Signal Transduction; D013154:Spleen / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D048069:Tumor Necrosis Factors / Q000378:metabolism; D020663:ras Guanine Nucleotide Exchange Factors / Q000502:physiology*
chemical_list: D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D053278:OX40 Ligand; C477240:Rasgrp4 protein, mouse; C504586:Tnfsf4 protein, mouse; D048069:Tumor Necrosis Factors; D020663:ras Guanine Nucleotide Exchange Factors; D007371:Interferon-gamma; D019009:Proto-Oncogene Proteins c-kit