title: T cell receptor stimulation impairs IL-7 receptor signaling by inducing expression of the microRNA miR-17 to target Janus kinase 1.
abstract: T cell receptor (TCR)-mediated inhibition of interleukin-7 (IL-7) signaling is important for lineage fate determination in the thymus and for T cell survival in the periphery because uninterrupted IL-7 signaling results in T cell death. The initial event in IL-7 signaling is the transactivation of Janus kinases 1 and 3 (Jak1 and Jak3), which are associated with the cytosolic tails of the IL-7 receptor α chain (IL-7Rα) and the γc subunit, the two cell surface proteins that constitute IL-7R. We found that Jak1 is a highly unstable protein with a half-life of only 1.5 hours, so that continuous Jak1 protein synthesis is required to maintain Jak1 protein in sufficient abundance to support IL-7 signaling. However, we also found that Jak1 protein synthesis was acutely reduced by TCR-responsive microRNAs in the miR-17 family, which targeted Jak1 mRNA (messenger RNA) to inhibit its translation. Thus, this study identifies a molecular mechanism by which TCR engagement acutely disrupts IL-7 signaling.
authors.affiliation: Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, 9000 Rockville Pike, Bethesda, MD 20892, USA.
authors.forename: Gil
authors.initials: G
authors.lastname: Katz
authors.affiliation: Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, 9000 Rockville Pike, Bethesda, MD 20892, USA.
authors.forename: Leonid A
authors.initials: LA
authors.lastname: Pobezinsky
authors.affiliation: Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, 9000 Rockville Pike, Bethesda, MD 20892, USA.
authors.forename: Susanna
authors.initials: S
authors.lastname: Jeurling
authors.affiliation: Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, 9000 Rockville Pike, Bethesda, MD 20892, USA.
authors.forename: Miho
authors.initials: M
authors.lastname: Shinzawa
authors.affiliation: Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, 9000 Rockville Pike, Bethesda, MD 20892, USA.
authors.forename: Francois
authors.initials: F
authors.lastname: Van Laethem
authors.affiliation: Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, 9000 Rockville Pike, Bethesda, MD 20892, USA. singera@mail.nih.gov.
authors.forename: Alfred
authors.initials: A
authors.lastname: Singer
mesh_terms: D000818:Animals; D015153:Blotting, Western; D005434:Flow Cytometry; D005786:Gene Expression Regulation / Q000276:immunology*; D047468:Immunoprecipitation; D053613:Janus Kinase 1 / Q000096:biosynthesis / Q000235:genetics*; D008156:Luciferases; D051379:Mice; D035683:MicroRNAs / Q000378:metabolism*; D012333:RNA, Messenger / Q000037:antagonists & inhibitors*; D060888:Real-Time Polymerase Chain Reaction; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*; D020395:Receptors, Interleukin-7 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction / Q000276:immunology*
chemical_list: D035683:MicroRNAs; C543614:Mirn17 microRNA, mouse; D012333:RNA, Messenger; D011948:Receptors, Antigen, T-Cell; D020395:Receptors, Interleukin-7; D008156:Luciferases; C507905:Jak1 protein, mouse; D053613:Janus Kinase 1