Background JIA is a heterogenous group of rheumatic conditions characterized by local inflammation and destruction of the joint space. Pro-inflammatory cytokines derived from T cells are considered culprits of disease. We have recently shown that some of these cytokines directly come from a distinct subset of T cells expressing CD31, an adhesion molecule normally expressed by granulocytes and endothelial cells.
Objectives In the present work, we examined whether the array of cytokines in blood and synovial fluid of patients are the same array produced by CD8+ T cells activation through CD31 ligation independent of the TCR. We propose that CD31-driven cytokine production by T cells is a self-perpetuating mechanism of local and systemic inflammation in JIA.
Methods Following informed consent/assent, blood and/or synovial fluid were collected from children with oligoarticular and polyarticular JIA. Similar blood samples were also collected from healthy subjects. Cytokine composition of the plasma and/or fluid was determined by multiplex analysis. Phenotypes of mononuclear cells in blood and synovial fluid were examined by multicolor flow cytometry. Drawing from the results of the multiplex assay, receptor crosslinking bioassays for cytokine production were performed using CD31+ primary T cells, and T lymphoid cell lines.
Results As expected, the overall cytokine signature of JIA is characterized by the dominance of IL-6, IL-10 and TNFα. Patients with oligoarticular disease showed higher levels of IFNγ and IL-17 family cytokines than those with polyarticular disease. Both types of patients however showed a similar cellular signature characterized by T cells deficient in CD4, CD8, and CD28, but expressing CD31. Results of CD31 cross-linking bioassays, using either specific antibody or its recombinant ligand CD38, showed high levels of induction of IL-2, IL-17, and IFNγ. Specificity of CD31-driven, TCR-independent cytokine production was verified by similar bioassays using somatic T cell line mutants deficient in TCR or in TCR/CD3 complex, but are both CD31+. The observed cytokine production was associated with phosphorylation of classical T cell-signaling substrates indicating CD31 ligation effectively pass the TCR-driven route of activation.
Conclusions Our data show that the cytokine profile of oligoarticular JIA is distinct with the dominance of IFNγ and IL17. CD31-driven induction of these cytokines in a TCR-independent manner indicates maladaptive T cell function in JIA. Further investigation on the relevance of IFNγ and IL-17 to disease activity/clinical outcomes, and the CD31 signaling cascade will pave way to innovations in immunotherapy in JIA.
Acknowledgements This work is supported by grants from the Nancy Taylor Foundation for Chronic Diseases, and the National Institutes of Health (T32 AR052282). Authors have no financial conflicts of interest.
Disclosure of Interest None declared