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

Abstract

AbstractHow pathogenic 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 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 auto-antigen exposure in vivo. The enhanced autoreactivity was associated with upregulation of IL-6 cytokine signaling machinery, which might in part be attributable 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 hyper-responsive to IL-6 receptor signaling. Consistent with findings from SKGNur mice, SOCS3 expression was similarly downregulated 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.Significance StatementHow arthritis-causing T cells trigger rheumatoid arthritis (RA) is not understood since it is difficult to differentiate T cells activated by inflammation in arthritic joints from those activated through their TCR by self-antigens. We developed a model to identify and study antigen-specific T cell responses in arthritis. Nur77—a specific marker of TCR signaling—was used to identify antigen-activated CD4 T cells in the SKG arthritis model and patients with RA. Nur77 could distinguish highly arthritogenic and autoreactive T cells in SKG mice. The enhanced autoreactivity was associated with increased IL-6-receptor-signaling, likely contributing to their arthritogenicity. These data highlight a functional correlate between Nur77 expression, arthritogenic T cell populations, and heightened IL-6 sensitivity in SKG mice with translatable implications for human RA.