Jeffery, LE;
Henley, P;
Marium, N;
Filer, A;
Sansom, DM;
Hewison, M;
Raza, K;
(2017)
Decreased sensitivity to 1,25-dihydroxyvitamin D3 in T cells from the rheumatoid joint.
Journal of Autoimmunity
10.1016/j.jaut.2017.10.001.
(In press).
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Abstract
1,25-dihydroxyvitaminD3 (1,25(OH)2D3), has potent anti-inflammatory effects, including suppression of IL-17 + and IFNγ+ 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+IFNγ-) and Th17.1 cells (IL-17+IFNγ+) from SF compared to those from blood, and had no effect on SF CD4+ or CD8+ IFNγ+ 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 IFNγ 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 IFNγ 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.
| Type: | Article |
|---|---|
| Title: | Decreased sensitivity to 1,25-dihydroxyvitamin D3 in T cells from the rheumatoid joint |
| Location: | England |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1016/j.jaut.2017.10.001 |
| Publisher version: | https://doi.org/10.1016/j.jaut.2017.10.001 |
| Language: | English |
| Additional information: | This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). |
| Keywords: | Peripheral blood, Rheumatoid arthritis, Synovial fluid, T cell, Vitamin D, Vitamin D receptor |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Infection and Immunity |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10041121 |
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