TCR-independent activation of T-cells through CD31 triggering as an etiology of cytokine production in juvenile idiopathic arthritis (JIA). (HUM7P.311)

Pro-inflammatory cytokines in the blood and synovium are key actors in JIA pathology. We recently reported that JIA patients have an over abundance of prematurely senescent CD8+ T cells expressing CD31, an adhesion molecule expressed by granulocytes and endothelial cells. CD31 triggering alone is sufficient to activate such senescent T cells. This study examined whether cytokine profile in JIA may be derived from T cell activation through CD31 ligation independent of the TCR. Results showed a cytokine signature of JIA characterized by dominance of IL-6, IL-10 and TNFα. Notably, patients with oligoarticular JIA showed higher levels of IFNγ and IL-17 family cytokines than those with polyarticular JIA. All patients also had a novel subset of T cells deficient in CD4, CD8, and CD28, but expressing CD31. Cross-linking bioassays, using anti-CD31 or its ligand CD38, show high levels of induction of IL-2, IL-17, and IFNγ. This CD31-driven, TCR-independent cytokine production was also verified by using somatic T cell line mutants that lack TCR and TCR/CD3, respectively, but both are CD31+. The observed cytokine production was associated with the phosphorylation of the signaling substrates ZAP70, cAbl, and p65-NFΚB. TCR independent, CD31-driven induction of these cytokines suggests maladaptive T cell function in JIA. Further investigation on the relevance of IFNγ and IL-17 to disease activity, and the CD31 signaling pathway may allow for innovations in immunotherapy.