CD117+ Dendritic and Mast Cells Are Dependent on RasGRP4 to Function as Accessory Cells for Optimal Natural Killer Cell-Mediated Responses to Lipopolysaccharide

• Published in: PloS one Vol. 11; no. 3; p. e0151638
• Main Authors: Zhou, Saijun, Tanaka, Kumiko, O'Keeffe, Meredith, Qi, Miao, El-Assaad, Fatima, Weaver, James C, Chen, Gang, Weatherall, Christopher, Wang, Ying, Giannakopoulos, Bill, Chen, Liming, Yu, DeMint, Hamilton, Matthew J, Wensing, Lislaine A, Stevens, Richard L, Krilis, Steven A
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 16.03.2016; Public Library of Science (PLoS)
• Subjects: Accessory cells; Animals; Antigen-presenting cells; Arthritis; Biology and life sciences; Bone marrow; Calcium; Cloning; Coculture Techniques; Cytokines; Dendritic cells; Dendritic Cells - immunology; Diglycerides; Endocrinology; Guanine; Guanine nucleotide exchange factor; Hormones; Hospitals; Immune response; Immune system; Immunity; Immunology; In vivo methods and tests; Infectious diseases; Innate immunity; Interferon; Interferon-gamma - metabolism; Intracellular; Intracellular signalling; Killer Cells, Natural - immunology; Laboratories; Ligands; Lipopolysaccharides; Lipopolysaccharides - pharmacology; Mast cells; Mast Cells - immunology; Medicine; Medicine and health sciences; Membrane Glycoproteins - metabolism; Metabolism; Mice; Mice, Inbred C57BL; mRNA; Natural killer cells; Optimization; Pharmacy; Proteins; Proto-Oncogene Proteins c-kit - immunology; ras Guanine Nucleotide Exchange Factors - physiology; Research and Analysis Methods; Rodents; Signal Transduction; Spleen; Spleen - cytology; Spleen - drug effects; Spleen - immunology; Tumor Necrosis Factors - metabolism; γ-Interferon; Australia; United States > US; China; New South Wales Australia
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0151638

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.