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

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


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autoimmunity
  • Cell Movement / genetics
  • Cell Movement / immunology
  • Clonal Selection, Antigen-Mediated / genetics*
  • Clonal Selection, Antigen-Mediated / immunology*
  • Disease Models, Animal
  • Dual Specificity Phosphatase 6 / metabolism
  • Encephalomyelitis, Autoimmune, Experimental / genetics
  • Encephalomyelitis, Autoimmune, Experimental / immunology
  • Encephalomyelitis, Autoimmune, Experimental / pathology
  • Gene Deletion
  • Immune Tolerance / genetics*
  • Immunization
  • Lysophospholipids / immunology
  • MAP Kinase Signaling System
  • Mice
  • Mice, Knockout
  • MicroRNAs / genetics*
  • Oligonucleotides / genetics
  • RNA Interference
  • Receptors, Antigen, T-Cell / metabolism
  • Signal Transduction
  • Sphingosine / analogs & derivatives
  • Sphingosine / immunology
  • T-Lymphocyte Subsets / immunology*
  • T-Lymphocyte Subsets / metabolism*
  • Thymocytes / immunology
  • Thymocytes / metabolism


  • Lysophospholipids
  • MicroRNAs
  • Oligonucleotides
  • Receptors, Antigen, T-Cell
  • mirn181 microRNA, mouse
  • sphingosine 1-phosphate
  • Dual Specificity Phosphatase 6
  • Dusp6 protein, mouse
  • Sphingosine