TY - JOUR
T1 - Decreased sensitivity to 1,25-dihydroxyvitamin D3 in T cells from the rheumatoid joint
AU - Jeffery, Louisa
AU - Henley, Peter
AU - Marium, Nefisa
AU - Filer, Andrew
AU - Sansom, David M
AU - Hewison, Martin
AU - Raza, Karim
N1 - Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.
PY - 2018/3
Y1 - 2018/3
N2 - 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.
AB - 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.
KW - T cell
KW - Vitamin D receptor
KW - Vitamin D
KW - Rheumatoid arthritis
KW - Synovial fluid
KW - Peripheral blood
U2 - 10.1016/j.jaut.2017.10.001
DO - 10.1016/j.jaut.2017.10.001
M3 - Article
C2 - 29066221
SN - 0896-8411
VL - 88
SP - 50
EP - 60
JO - Journal of Autoimmunity
JF - Journal of Autoimmunity
ER -