Rare IL-17A+ Lymphocytes in the Pathogenesis of Spondyloarthritis.
Hossain, Imtiyaz N.
- Spondyloarthritis is a family of rheumatic diseases characterized by inflammation in the spine, peripheral joints, skin, intestine and other organs. Systemic overexpression of IL-23 via hydrodynamic minicircle injection in adult B10.RIII mice induces a spondyloarthritis-like disease with high expression of IL-17A, a pro-inflammatory cytokine downstream of IL-23. A previous study identified a rare ... read moresubset of CD3+CD4-CD8- Double Negative (DN) tissue-resident T cells as the major source of IL-17A in this model. Here we characterize these DN T cells further as γδ T cells and DN αβ T cells and show that they require co-stimulation with IL-1β and IL-23 for IL-17A induction. IL1R1-/- and IL23R-/- mice had largely similar frequencies of γδ and DN αβ T cells compared with wild type controls, demonstrating that these cytokine receptors control the function but not the development of γδ and DN αβ T cells. In γδTCR-/- mice, IL-17A secreting DN αβ T cells were expanded, consistent with numerical and functional compensation. C57BL/6 mice, in contrast to B10.RIII mice, did not develop spondyloarthritis upon IL-23 minicircle injection. C57BL/6 and B10.RIII mice had similar frequencies of γδ and DN αβ T cells but IL-17A production by DN αβ T cells was significantly higher in disease-prone B10.RIII mice. Oral treatment of B10.RIII mice with broad-spectrum antibiotics also prevented the development of IL-23 minicircle-induced disease. While antibiotics had no major impact on the frequency of γδ and DN αβ T cells, IL-17A secretion by γδ and DN αβ T cells was significantly reduced. Further investigations are required to elucidate how intestinal microbiota control IL-17A secretion by γδ and DN αβ T cells, which may lead to novel therapies for patients with spondyloarthritis.read less