title: Epistasis between microRNAs 155 and 146a during T cell-mediated antitumor immunity.
abstract: An increased understanding of antitumor immunity is necessary for improving cell-based immunotherapies against human cancers. Here, we investigated the roles of two immune system-expressed microRNAs (miRNAs), miR-155 and miR-146a, in the regulation of antitumor immune responses. Our results indicate that miR-155 promotes and miR-146a inhibits interferon γ (IFNγ) responses by T cells and reduces solid tumor growth in vivo. Using a double-knockout (DKO) mouse strain deficient in both miR-155 and miR-146a, we have also identified an epistatic relationship between these two miRNAs. DKO mice had defective T cell responses and tumor growth phenotypes similar to miR-155(-/-) mice. Further analysis of the T cell compartment revealed that miR-155 modulates IFNγ expression through a mechanism involving repression of Ship1. Our work reveals critical roles for miRNAs in the reciprocal regulation of CD4(+) and CD8(+) T cell-mediated antitumor immunity and demonstrates the dominant nature of miR-155 during its promotion of immune responses.
authors.affiliation: Division of Microbiology and Immunology, Department of Pathology, University of Utah, Salt Lake City, UT 84112, USA.
authors.forename: Thomas B
authors.initials: TB
authors.lastname: Huffaker
authors.forename: Ruozhen
authors.initials: R
authors.lastname: Hu
authors.forename: Marah C
authors.initials: MC
authors.lastname: Runtsch
authors.forename: Erin
authors.initials: E
authors.lastname: Bake
authors.forename: Xinjian
authors.initials: X
authors.lastname: Chen
authors.forename: Jimmy
authors.initials: J
authors.lastname: Zhao
authors.forename: June L
authors.initials: JL
authors.lastname: Round
authors.forename: David
authors.initials: D
authors.lastname: Baltimore
authors.forename: Ryan M
authors.initials: RM
authors.lastname: O'Connell
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D004843:Epistasis, Genetic / Q000235:genetics / Q000276:immunology*; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007111:Immunity, Cellular; D000072181:Inositol Polyphosphate 5-Phosphatases; D007371:Interferon-gamma / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D035683:MicroRNAs / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D009374:Neoplasms, Experimental / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics / Q000276:immunology / Q000378:metabolism
chemical_list: D035683:MicroRNAs; C534190:Mirn146 microRNA, mouse; C532623:Mirn155 microRNA, mouse; D007371:Interferon-gamma; D010744:Phosphoric Monoester Hydrolases; D000072181:Inositol Polyphosphate 5-Phosphatases; C000606430:INPP5D protein, human; C000606433:Inpp5d protein, mouse; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases