Increased ERK1/2 activation leads to sustained T cell receptor signaling in rheumatoid arthritis (49.8)

Abstract

Abstract Immune responses to citrullinated neoantigens indicate a tolerance defect in rheumatoid arthritis (RA). We examined the hypothesis that abnormal TCR signaling in RA T cells lowers the activation threshold. T cells from 33 seropositive RA patients and 33 controls were stimulated by CD3/CD28 crosslinking or superantigen-coated dendritic cells. Activation-induced signaling was quantified by PhosFlow, Western blotting, and confocal microscopy. Basal as well as post-stimulation p-ERK was higher in naïve, memory and effector CD4 and CD8 T cells from RA patients compared to controls (p<0.01 to p<0.001). Increased ERK phosphorylation was also observed upon PMA/ionomycin stimulation suggesting a defect distal of early TCR signals. Phosphorylation of ZAP70 and NFk-B was only elevated at late time points, and this increase was completely amenable to MEK1 and ERK inhibitors. Increased ERK responsiveness led to delayed recruitment of SHP-1 to the immunological synapse of RA T cells and lowered the TCR threshold to suboptimal stimulation. Increased ERK responsiveness was also a characteristic finding in the SKG mouse model of RA and preceded clinical symptoms. MEK-1 inhibition with subtherapeutic doses significantly delayed the onset of less severe disease. We propose that increased ERK activity tunes TCR thresholds to impair tolerance mechanism and induce autoimmunity in RA. Supported by RO1-AR41974 & AI 44142.