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

Jeffery, Louisa E, Henley, Peter, Marium, Nefisa, Filer, Andrew, Sansom, David M, Hewison, Martin and Raza, Karim (2018) Decreased sensitivity to 1,25-dihydroxyvitamin D3 in T cells from the rheumatoid joint. Journal of autoimmunity, 88. pp. 50-60. ISSN 1095-9157.

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1,25-dihydroxyvitaminD (1,25(OH)D), 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)D 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)D 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)D to suppress pre-existing cytokines. However, 1,25(OH)D was most effective at suppressing de novo IL-17 and IFNγ induction. Correspondingly, T cell responses to 1,25(OH)D 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)D 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)D responses in memory T cells may provide a new strategy for treatment of inflammatory diseases such as RA.

Item Type: Article
Subjects: WD Diseases and disorders of systemic, metabolic or environmental origin > WD811 Rheumatology
Divisions: Ambulatory Care > Rheumatology
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Depositing User: Mrs Noomi Tyholdt-Pidgley
Date Deposited: 05 Jun 2019 15:06
Last Modified: 05 Jun 2019 15:06

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