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T Cell Receptor-Independent, CD31/IL-17A-Driven Inflammatory Axis Shapes Synovitis in Juvenile Idiopathic Arthritis.

Publication ,  Journal Article
Ferguson, ID; Griffin, P; Michel, JJ; Yano, H; Gaffen, SL; Mueller, RG; Dvergsten, JA; Piganelli, JD; Rosenkranz, ME; Kietz, DA; Vallejo, AN
Published in: Front Immunol
2018

T cells are considered autoimmune effectors in juvenile idiopathic arthritis (JIA), but the antigenic cause of arthritis remains elusive. Since T cells comprise a significant proportion of joint-infiltrating cells, we examined whether the environment in the joint could be shaped through the inflammatory activation by T cells that is independent of conventional TCR signaling. We focused on the analysis of synovial fluid (SF) collected from children with oligoarticular and rheumatoid factor-negative polyarticular JIA. Cytokine profiling of SF showed dominance of five molecules including IL-17A. Cytometric analysis of the same SF samples showed enrichment of αβT cells that lacked both CD4 and CD8 co-receptors [herein called double negative (DN) T cells] and also lacked the CD28 costimulatory receptor. However, these synovial αβT cells expressed high levels of CD31, an adhesion molecule that is normally employed by granulocytes when they transit to sites of injury. In receptor crosslinking assays, ligation of CD31 alone on synovial CD28nullCD31+ DN αβT cells effectively and sufficiently induced phosphorylation of signaling substrates and increased intracytoplasmic stores of cytokines including IL-17A. CD31 ligation was also sufficient to induce RORγT expression and trans-activation of the IL-17A promoter. In addition to T cells, SF contained fibrocyte-like cells (FLC) expressing IL-17 receptor A (IL-17RA) and CD38, a known ligand for CD31. Stimulation of FLC with IL-17A led to CD38 upregulation, and to production of cytokines and tissue-destructive molecules. Addition of an oxidoreductase analog to the bioassays suppressed the CD31-driven IL-17A production by T cells. It also suppressed the downstream IL-17A-mediated production of effectors by FLC. The levels of suppression of FLC effector activities by the oxidoreductase analog were comparable to those seen with corticosteroid and/or biologic inhibitors to IL-6 and TNFα. Collectively, our data suggest that activation of a CD31-driven, αβTCR-independent, IL-17A-mediated T cell-FLC inflammatory circuit drives and/or perpetuates synovitis. With the notable finding that the oxidoreductase mimic suppresses the effector activities of synovial CD31+CD28null αβT cells and IL-17RA+CD38+ FLC, this small molecule could be used to probe further the intricacies of this inflammatory circuit. Such bioactivities of this small molecule also provide rationale for new translational avenue(s) to potentially modulate JIA synovitis.

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Published In

Front Immunol

DOI

EISSN

1664-3224

Publication Date

2018

Volume

9

Start / End Page

1802

Location

Switzerland

Related Subject Headings

  • T-Lymphocytes
  • T-Lymphocyte Subsets
  • Synovitis
  • Receptors, Antigen, T-Cell
  • Proto-Oncogene Proteins c-abl
  • Promoter Regions, Genetic
  • Platelet Endothelial Cell Adhesion Molecule-1
  • Phosphorylation
  • Oxidoreductases
  • Metalloporphyrins
 

Citation

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Chicago
ICMJE
MLA
NLM
Ferguson, I. D., Griffin, P., Michel, J. J., Yano, H., Gaffen, S. L., Mueller, R. G., … Vallejo, A. N. (2018). T Cell Receptor-Independent, CD31/IL-17A-Driven Inflammatory Axis Shapes Synovitis in Juvenile Idiopathic Arthritis. Front Immunol, 9, 1802. https://doi.org/10.3389/fimmu.2018.01802
Ferguson, Ian D., Patricia Griffin, Joshua J. Michel, Hiroshi Yano, Sarah L. Gaffen, Robert G. Mueller, Jeffrey A. Dvergsten, et al. “T Cell Receptor-Independent, CD31/IL-17A-Driven Inflammatory Axis Shapes Synovitis in Juvenile Idiopathic Arthritis.Front Immunol 9 (2018): 1802. https://doi.org/10.3389/fimmu.2018.01802.
Ferguson ID, Griffin P, Michel JJ, Yano H, Gaffen SL, Mueller RG, et al. T Cell Receptor-Independent, CD31/IL-17A-Driven Inflammatory Axis Shapes Synovitis in Juvenile Idiopathic Arthritis. Front Immunol. 2018;9:1802.
Ferguson, Ian D., et al. “T Cell Receptor-Independent, CD31/IL-17A-Driven Inflammatory Axis Shapes Synovitis in Juvenile Idiopathic Arthritis.Front Immunol, vol. 9, 2018, p. 1802. Pubmed, doi:10.3389/fimmu.2018.01802.
Ferguson ID, Griffin P, Michel JJ, Yano H, Gaffen SL, Mueller RG, Dvergsten JA, Piganelli JD, Rosenkranz ME, Kietz DA, Vallejo AN. T Cell Receptor-Independent, CD31/IL-17A-Driven Inflammatory Axis Shapes Synovitis in Juvenile Idiopathic Arthritis. Front Immunol. 2018;9:1802.

Published In

Front Immunol

DOI

EISSN

1664-3224

Publication Date

2018

Volume

9

Start / End Page

1802

Location

Switzerland

Related Subject Headings

  • T-Lymphocytes
  • T-Lymphocyte Subsets
  • Synovitis
  • Receptors, Antigen, T-Cell
  • Proto-Oncogene Proteins c-abl
  • Promoter Regions, Genetic
  • Platelet Endothelial Cell Adhesion Molecule-1
  • Phosphorylation
  • Oxidoreductases
  • Metalloporphyrins