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

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

Author information

1
Rosalind Russell and Ephraim P. Engleman Rheumatology Research Center, Division of Rheumatology, Department of Medicine, University of California, San Francisco, CA 94143.
2
Institute for Computational Health Sciences, University of California, San Francisco, CA 94143.
3
Department of Pediatrics, University of California, San Francisco, CA 94143.
4
Department of Orthopedic Surgery, University of California, San Francisco, CA 94143.
5
Rosalind Russell and Ephraim P. Engleman Rheumatology Research Center, Division of Rheumatology, Department of Medicine, University of California, San Francisco, CA 94143; Arthur.Weiss@ucsf.edu.
6
Howard Hughes Medical Institute, University of California, San Francisco, CA 94143.

Abstract

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

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