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


ABSTRACT: 1,25-dihydroxyvitaminD3 (1,25(OH)2D3), has potent anti-inflammatory effects, including suppression of IL-17 + and IFN?+ 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)2D3 had significantly less suppressive effect on Th17 cells (IL-17+IFN?-) and Th17.1 cells (IL-17+IFN?+) from SF compared to those from blood, and had no effect on SF CD4+ or CD8+ IFN?+ T cell frequencies. Memory T cells (CD45RO+) predominate in SF, and 1,25(OH)2D3 had less effect on memory T cells relative to naïve (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? expression confirmed the ability of 1,25(OH)2D3 to suppress pre-existing cytokines. However, 1,25(OH)2D3 was most effective at suppressing de novo IL-17 and IFN? induction. Correspondingly, T cell responses to 1,25(OH)2D3 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)2D3 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)2D3 responses in memory T cells may provide a new strategy for treatment of inflammatory diseases such as RA.

PROVIDER: S-EPMC5854374 | BioStudies |

REPOSITORIES: biostudies

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