Activation of joint CD8+ TRM localize autoantibody mediated arthritis.
Background: In humans, upper respiratory infections have been associated with onset of Rheumatoid Arthritis. In mice, following viral infection, CD8+ T cells take up residence in joints and a portion become tissue resident memory cells (TRM). As these CD8+ TRM are not specific for a Rheumatoid Arthritis specific self-peptide, it is not clear if they contribute to disease activity. In the mouse uterus, re-activation of CD8+ TRM increases the permeability of the tissue to circulating antibodies. Utilizing the K/BxN serum transfer model, we demonstrate that local activation of CD8+ TRM generates persistent clinical arthritis at that site. Methods: C57BL/6 mice received adoptive transfer of OT-1 transgenic CD8+ T cells, whose cognate antigen is SIINFEKL peptide. The next day, they are infected with vesicular stomatitis virus encoding SIINFEKL. Acute infection resolves over the course of a few weeks, virus is cleared, but tissues are persistently populated by OT-1 CD8+ TRM. Naïve and OT-1 memory mice receive dose limited volumes of arthritogenic serum from K/BxN mice. Two days later, they receive an injection of SIINFEKL peptide in their left ankle and left knee to reactivate OT-1 TRM. Both ankles and wrists were scored for severity of clinical inflammation and their size was measured by calipers daily. After seven days, mice were sacrificed, ankles fixed and decalcified for histology, and knees collected for flow cytometry. Results: Persistent clinical inflammation and increased size was found in the left ankle of OT-1 memory mice injected with SIINFEKL, but not their right ankle, not in the left ankle of memory mice injected with an irrelevant peptide, and not in naïve mice that received SIINFEKL in their left ankle. By flow cytometry, in the left knee of OT-1 memory mice injected with SIINFEKL, there were more CD4+ T cells, CD8+ T cells, and B220+ B cells compared to their right knee, but also compared to the left knee of mice injected with an irrelevant peptide and compared to the knee of naïve mice injected with SIINFEKL. Conclusions: Joint CD8+ TRM activation enhances autoantibody mediated inflammation locally.