IL-21R signaling is critical for induction of spontaneous experimental autoimmune encephalomyelitis

J Clin Invest. 2015 Nov 2;125(11):4011-20. doi: 10.1172/JCI75933. Epub 2015 Sep 28.


IL-17-producing CD4+ T cells (Th17 cells) have well-described pathogenic roles in tissue inflammation and autoimmune diseases, such as experimental autoimmune encephalomyelitis (EAE); however, the involvement of IL-21 in these processes has remained controversial. While IL-21 is an essential autocrine amplification factor for differentiation of Th17 cells, the loss of IL-21 or IL-21 receptor (IL-21R) does not protect mice from actively induced EAE. Here, we utilized a transgenic EAE mouse model, in which T and B cells overexpress receptors for myelin oligodendrocyte glycoprotein (MOG) (referred to as 2D2xTH mice), and demonstrated that IL-21 is critical for the development of a variant form of spontaneous EAE in these animals. Il21r deletion in 2D2xTH mice reduced the incidence and severity of spontaneous EAE, which was associated with a defect in Th17 cell generation. Moreover, IL-21R deficiency limited IL-23R expression on Th17 cells and inhibited expression of key molecules involved in the generation of pathogenic Th17 cells. Conversely, loss of IL-23R in 2D2xTH mice resulted in complete resistance to the development of spontaneous EAE. Our data identify a previously unappreciated role for IL-21 in EAE and reveal that IL-21-mediated signaling supports generation and stabilization of pathogenic Th17 cells and development of spontaneous autoimmunity.

Publication types

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

MeSH terms

  • Animals
  • Antigen Presentation
  • Cells, Cultured
  • Disease Susceptibility
  • Encephalomyelitis, Autoimmune, Experimental / immunology
  • Encephalomyelitis, Autoimmune, Experimental / pathology
  • Encephalomyelitis, Autoimmune, Experimental / physiopathology*
  • Interferon-gamma / biosynthesis
  • Interferon-gamma / genetics
  • Interleukin-21 Receptor alpha Subunit / deficiency
  • Interleukin-21 Receptor alpha Subunit / genetics
  • Interleukin-21 Receptor alpha Subunit / physiology*
  • Interleukins / physiology*
  • Lymphocyte Activation
  • Lymphopoiesis
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Myelin-Oligodendrocyte Glycoprotein / immunology
  • Peptide Fragments / immunology
  • Receptors, Interleukin / biosynthesis
  • Receptors, Interleukin / deficiency
  • Receptors, Interleukin / genetics
  • Signal Transduction
  • Specific Pathogen-Free Organisms
  • Th17 Cells / immunology*


  • Il21r protein, mouse
  • Interleukin-21 Receptor alpha Subunit
  • Interleukins
  • Myelin-Oligodendrocyte Glycoprotein
  • Peptide Fragments
  • Receptors, Interleukin
  • interleukin-23 receptor, mouse
  • myelin oligodendrocyte glycoprotein (35-55)
  • Interferon-gamma
  • interleukin-21