title: mir-181a-1/b-1 Modulates Tolerance through Opposing Activities in Selection and Peripheral T Cell Function.
abstract: Understanding the consequences of tuning TCR signaling on selection, peripheral T cell function, and tolerance in the context of native TCR repertoires may provide insight into the physiological control of tolerance. In this study, we show that genetic ablation of a natural tuner of TCR signaling, mir-181a-1/b-1, in double-positive thymocytes dampened TCR and Erk signaling and increased the threshold of positive selection. Whereas mir-181a-1/b-1 deletion in mice resulted in an increase in the intrinsic reactivity of naive T cells to self-antigens, it did not cause spontaneous autoimmunity. Loss of mir-181a-1/b-1 dampened the induction of experimental autoimmune encephalomyelitis and reduced basal TCR signaling in peripheral T cells and their migration from lymph nodes to pathogenic sites. Taken together, these results demonstrate that tolerance can be modulated by microRNA gene products through the control of opposing activities in T cell selection and peripheral T cell function.
authors.affiliation: Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305; Baxter Laboratory in Stem Cell Biology, Stanford University School of Medicine, Stanford, CA 94305; Program of Immunology, Stanford University School of Medicine, Stanford, CA 94305;
authors.forename: Steven A
authors.initials: SA
authors.lastname: Schaffert
authors.affiliation: Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305; Baxter Laboratory in Stem Cell Biology, Stanford University School of Medicine, Stanford, CA 94305;
authors.forename: Christina
authors.initials: C
authors.lastname: Loh
authors.affiliation: Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305; Baxter Laboratory in Stem Cell Biology, Stanford University School of Medicine, Stanford, CA 94305;
authors.forename: Song
authors.initials: S
authors.lastname: Wang
authors.affiliation: Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305; Baxter Laboratory in Stem Cell Biology, Stanford University School of Medicine, Stanford, CA 94305; Program of Immunology, Stanford University School of Medicine, Stanford, CA 94305;
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Arnold
authors.affiliation: Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305;
authors.forename: Robert C
authors.initials: RC
authors.lastname: Axtell
authors.affiliation: Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305;
authors.forename: Evan W
authors.initials: EW
authors.lastname: Newell
authors.affiliation: Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305; Baxter Laboratory in Stem Cell Biology, Stanford University School of Medicine, Stanford, CA 94305; Program of Immunology, Stanford University School of Medicine, Stanford, CA 94305;
authors.forename: Garry
authors.initials: G
authors.lastname: Nolan
authors.affiliation: Department of Microbiology and Immunology, University of California San Francisco, San Francisco, CA 94143; Sandler Asthma Basic Research Center, University of California San Francisco, San Francisco, CA 94143;
authors.forename: K Mark
authors.initials: KM
authors.lastname: Ansel
authors.affiliation: Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305; Program of Immunology, Stanford University School of Medicine, Stanford, CA 94305; Howard Hughes Medical Institute, San Francisco, CA 94158; and.
authors.forename: Mark M
authors.initials: MM
authors.lastname: Davis
authors.affiliation: Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305;
authors.forename: Lawrence
authors.initials: L
authors.lastname: Steinman
authors.affiliation: Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305; Baxter Laboratory in Stem Cell Biology, Stanford University School of Medicine, Stanford, CA 94305; Achelois Pharmaceuticals, Inc., San Francisco, CA 94107 chen@acheloispharma.com.
authors.forename: Chang-Zheng
authors.initials: CZ
authors.lastname: Chen
mesh_terms: D000818:Animals; D015551:Autoimmunity; D002465:Cell Movement / Q000235:genetics / Q000276:immunology; D060966:Clonal Selection, Antigen-Mediated / Q000235:genetics* / Q000276:immunology*; D004195:Disease Models, Animal; D054642:Dual Specificity Phosphatase 6 / Q000378:metabolism; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics / Q000276:immunology / Q000473:pathology; D017353:Gene Deletion; D007108:Immune Tolerance / Q000235:genetics*; D007114:Immunization; D008246:Lysophospholipids / Q000276:immunology; D020935:MAP Kinase Signaling System; D051379:Mice; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics*; D009841:Oligonucleotides / Q000235:genetics; D034622:RNA Interference; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D015398:Signal Transduction; D013110:Sphingosine / Q000031:analogs & derivatives / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism*; D060168:Thymocytes / Q000276:immunology / Q000378:metabolism
chemical_list: D008246:Lysophospholipids; D035683:MicroRNAs; D009841:Oligonucleotides; D011948:Receptors, Antigen, T-Cell; C529100:mirn181 microRNA, mouse; C060506:sphingosine 1-phosphate; D054642:Dual Specificity Phosphatase 6; C517036:Dusp6 protein, mouse; D013110:Sphingosine