Background/Purpose: T cells are considered effectors of immunopathology in JIA. In previous work, we reported dominance of senescent CD8T cells in synovial fluid of children with oligoarticular (oligo-) and polyarticular (poly-) JIA disease. Here, we examined for additional effector cells and how they shape the inflammatory microenvironment of the synovium.

Methods: Healthy children, children with oligo- and poly-JIA, and their legal guardians provided informed assent/consent. Blood samples were obtained, and where medically indicated, synovial fluids were collected from JIA patients. Cell populations were examined by flow cytometry. Cell cultures and bioassays of cell activation were performed using previously established protocols. Cytokine profiles of plasma, synovial fluids, and culture supernatants were determined by the Luminex system.

Results: The local and systemic cytokine signatures of JIA were dominated by five molecules including TNFα and IL-17. The corresponding cellular signatures included senescent CD31⁺ CD8T cells, and CD31⁺ double negative (DN) T cells that lack both CD4 and CD8. In synovial fluid, large numbers of fibrocyte-like cells (FLC) expressing procollagen, proline-4-hydroxylase, IL-17 receptor A, and the CD31 ligand CD38, also abound. Ligation of CD31 either with specific antibody or recombinant CD38, independent of the TCR, on synovial CD8T and DNT cells was sufficient to induce production of TNFα and IL-17. CD31 ligation alone was also sufficient to transactivate the IL-17 gene promoter, and the IL-17 gene transcription factor RORγT. Incubation of FLC with TNFα, IL-17, or both led to the induction of vascular endothelial growth factor, a known propagator of tissue inflammation, and three species of matrix metalloproteinases known to directly elicit cell/tissue damage. These T cell and FLC responses were abrogated by steroids, infliximab, tocolizumab, and a novel experimental small molecule inhibitor.

Conclusion: Collectively, our data indicate CD8T/DNT-FLC communication circuit via CD31 and IL-17. CD31-driven, TCR-independent induction of TNFα and IL-17 clearly demonstrate dysregulation of T cell effector function. Activation of FLC by T cell-derived TNFα and IL-17 amplifies synovial inflammatory processes. Further understanding of the control of this T cell-FLC circuit will pave way to innovative strategies to dampen immunopathology of JIA. 

[Authors have no conflicts of interest. This work is supported by grants from the Nancy Taylor Foundation and the NIH]

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/interaction-between-senescent-t-cells-and-fibrocyte-like-cells-through-cd31-tnf-and-il-17-create-a-tissue-destructive-environment-in-the-synovium-in-juvenile-idiopathic-arthritis/