Reporters of TCR signaling identify arthritogenic T cells in murine and human autoimmune arthritis

Proc Natl Acad Sci U S A. 2019 Sep 10;116(37):18517-18527. doi: 10.1073/pnas.1904271116. Epub 2019 Aug 27.


How pathogenic cluster of differentiation 4 (CD4) T cells in rheumatoid arthritis (RA) develop remains poorly understood. We used Nur77-a marker of T cell antigen receptor (TCR) signaling-to identify antigen-activated CD4 T cells in the SKG mouse model of autoimmune arthritis and in patients with RA. Using a fluorescent reporter of Nur77 expression in SKG mice, we found that higher levels of Nur77-eGFP in SKG CD4 T cells marked their autoreactivity, arthritogenic potential, and ability to more readily differentiate into interleukin-17 (IL-17)-producing cells. The T cells with increased autoreactivity, nonetheless had diminished ex vivo inducible TCR signaling, perhaps reflective of adaptive inhibitory mechanisms induced by chronic autoantigen exposure in vivo. The enhanced autoreactivity was associated with up-regulation of IL-6 cytokine signaling machinery, which might be attributable, in part, to a reduced amount of expression of suppressor of cytokine signaling 3 (SOCS3)-a key negative regulator of IL-6 signaling. As a result, the more autoreactive GFPhi CD4 T cells from SKGNur mice were hyperresponsive to IL-6 receptor signaling. Consistent with findings from SKGNur mice, SOCS3 expression was similarly down-regulated in RA synovium. This suggests that despite impaired TCR signaling, autoreactive T cells exposed to chronic antigen stimulation exhibit heightened sensitivity to IL-6, which contributes to the arthritogenicity in SKG mice, and perhaps in patients with RA.

Keywords: Nur77; T cells; antigen receptor signaling; autoimmunity; rheumatoid arthritis.

Publication types

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

MeSH terms

  • Adult
  • Aged
  • Animals
  • Arthritis, Experimental / immunology*
  • Arthritis, Experimental / pathology
  • Arthritis, Rheumatoid / immunology*
  • Arthritis, Rheumatoid / pathology
  • Arthritis, Rheumatoid / surgery
  • Biopsy
  • CD4-Positive T-Lymphocytes / immunology*
  • CD4-Positive T-Lymphocytes / metabolism
  • Cell Differentiation / immunology
  • Down-Regulation
  • Female
  • Genes, Reporter / genetics
  • Green Fluorescent Proteins / chemistry
  • Green Fluorescent Proteins / genetics
  • Humans
  • Interleukin-17 / metabolism
  • Interleukin-6 / immunology
  • Interleukin-6 / metabolism
  • Male
  • Mice
  • Mice, Transgenic
  • Middle Aged
  • Nuclear Receptor Subfamily 4, Group A, Member 1 / chemistry
  • Nuclear Receptor Subfamily 4, Group A, Member 1 / genetics
  • Receptors, Antigen, T-Cell / immunology
  • Receptors, Antigen, T-Cell / metabolism
  • Signal Transduction / immunology
  • Suppressor of Cytokine Signaling 3 Protein / immunology
  • Suppressor of Cytokine Signaling 3 Protein / metabolism
  • Synovectomy
  • Synovial Membrane / cytology
  • Synovial Membrane / immunology*
  • Synovial Membrane / metabolism
  • Synovial Membrane / pathology
  • Th17 Cells / immunology*
  • Th17 Cells / metabolism
  • Zymosan / administration & dosage
  • Zymosan / immunology


  • IL6 protein, human
  • Interleukin-17
  • Interleukin-6
  • Nr4a1 protein, mouse
  • Nuclear Receptor Subfamily 4, Group A, Member 1
  • Receptors, Antigen, T-Cell
  • SOCS3 protein, human
  • Socs3 protein, mouse
  • Suppressor of Cytokine Signaling 3 Protein
  • enhanced green fluorescent protein
  • interleukin-6, mouse
  • Green Fluorescent Proteins
  • Zymosan