Decreased sensitivity to 1,25-dihydroxyvitamin D3 in T cells from the rheumatoid joint

作者：Jeffery Louisa E; Henley Peter; Marium Nefisa; Filer Andrew; Sansom David M; Hewison Martin^*; Raza Karim

来源：Journal of Autoimmunity, 2018, 88: 50-60.

DOI：10.1016/j.jaut.2017.10.001

• Vitamin D
• Rheumatoid arthritis
• Synovial fluid
• Peripheral blood
• T cell
• Vitamin D receptor

1,25-dihydroxyvitaminD3 (1,25(OH)(2)D-3), has potent anti-inflammatory effects, including suppression of IL-17 + and IFN gamma+ T cells implicated in rheumatoid arthritis (RA), but efficacy at the site of active disease is unclear. To investigate this, T cells from synovial fluid (SF) and paired blood of patients with active RA were studied. 1,25(OH)(2)D-3 had significantly less suppressive effect on Th17 cells (IL-17+IFN gamma-) and Th17.1 cells (1-17+IFN gamma+) from SF compared to those from blood, and had no effect on SF CD4(+) or CD8(+) IFN gamma+ T cell frequencies. Memory T cells (CD45R0+) predominate in SF, and 1,25(OH)(2)D-3 had less effect on memory T cells relative to naive (CD45RA+) T cells. RT-PCR and flow cytometry showed that this was not due to decreased expression of the vitamin D receptOr or its transcription partners in memory T cells. Further studies using stimulated CD4(+) T cells sorted according to IL-17 and IFN gamma expression confirmed the ability of 1,25(OH)(2)D-3 to suppress pre-existing cytokines. However, 1,25(OH)(2)D-3 was most effective at suppressing de novo IL-17 and IFN gamma induction. Correspondingly, T cell responses to 1,25(OH)(2)D-3 correlated directly with capacity for phenotype change, which was lower in cells from SF compared to blood. These findings indicate that anti-inflammatory effects of 1,25(OH)(2)D-3 in active RA are impaired because of reduced effects on phenotype-committed, inflammatory memory T cells that are enriched in SF. Restoration of 1,25(OH)(2)D-3 responses in memory T cells may provide a new strategy for treatment of inflammatory diseases such as RA.

• 出版日期2018-3