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J Immunol. 2015 Aug 15;195(4):1470-9. doi: 10.4049/jimmunol.1401587. Epub 2015 Jul 10.

mir-181a-1/b-1 Modulates Tolerance through Opposing Activities in Selection and Peripheral T Cell Function.

Author information

1
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;
2
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;
3
Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305;
4
Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305;
5
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;
6
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.
7
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.

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.

PMID:
26163591
PMCID:
PMC4763610
DOI:
10.4049/jimmunol.1401587
[Indexed for MEDLINE]
Free PMC Article

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