Reporters of TCR signaling identify arthritogenic T cells in murine and human autoimmune arthritis.
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.
['Ashouri|Judith F|JF|', 'Hsu|Lih-Yun|LY|', 'Yu|Steven|S|', 'Rychkov|Dmitry|D|', 'Chen|Yiling|Y|', 'Cheng|Debra A|DA|', 'Sirota|Marina|M|', 'Hansen|Erik|E|', 'Lattanza|Lisa|L|', 'Zikherman|Julie|J|', 'Weiss|Arthur|A|']
D000328:Adult D000368:Aged D000818:Animals D001169:Arthritis, Experimental D001172:Arthritis, Rheumatoid D001706:Biopsy D015496:CD4-Positive T-Lymphocytes D002454:Cell Differentiation D015536:Down-Regulation D005260:Female D017930:Genes, Reporter D049452:Green Fluorescent Proteins D006801:Humans D020381:Interleukin-17 D015850:Interleukin-6 D008297:Male D051379:Mice D008822:Mice, Transgenic D008875:Middle Aged D057105:Nuclear Receptor Subfamily 4, Group A, Member 1 D011948:Receptors, Antigen, T-Cell D015398:Signal Transduction D000071223:Suppressor of Cytokine Signaling 3 Protein D000074402:Synovectomy D013583:Synovial Membrane D058504:Th17 Cells D015054:Zymosan
T cells autoimmunity rheumatoid arthritis Nur77 antigen receptor signaling