Anderson, A E, Swan, David, Wong, O Y, Buck, M, Eltherington, O, Harry, R A, Patterson, A M, Pratt, A G, Reynolds, G, Doran, J-P, Kirby, J A, Isaacs, J D and Hilkens, C M U (2016) Tolerogenic dendritic cells generated with dexamethasone and vitamin D3 regulate rheumatoid arthritis CD4 T cells partly via transforming growth factor-β1. Clinical and experimental immunology, 187 (1). pp. 113-123. ISSN 0009-9104
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Abstract
Abstract
Tolerogenic dendritic cells (tolDC) are a new immunotherapeutic tool for the treatment of rheumatoid arthritis (RA) and other autoimmune disorders. We have established a method to generate stable tolDC by pharmacological modulation of human monocyte-derived DC. These tolDC exert potent pro-tolerogenic actions on CD4 T cells. Lack of interleukin (IL)-12p70 production is a key immunoregulatory attribute of tolDC but does not explain their action fully. Here we show that tolDC express transforming growth factor (TGF)-β1 at both mRNA and protein levels, and that expression of this immunoregulatory cytokine is significantly higher in tolDC than in mature monocyte-derived DC. By inhibiting TGF-β1 signalling we demonstrate that tolDC regulate CD4 T cell responses in a manner that is at least partly dependent upon this cytokine. Crucially, we also show that while there is no significant difference in expression of TGF-βRII on CD4 T cells from RA patients and healthy controls, RA patient CD4 T cells are measurably less responsive to TGF-β1 than healthy control CD4 T cells [reduced TGF-β-induced mothers against decapentaplegic homologue (Smad)2/3 phosphorylation, forkhead box protein 3 (FoxP3) expression and suppression of (IFN)-γ secretion]. However, CD4 T cells from RA patients can, nonetheless, be regulated efficiently by tolDC in a TGF-β1-dependent manner. This work is important for the design and development of future studies investigating the potential use of tolDC as a novel immunotherapy for the treatment of RA.
| Item Type: | Article |
|---|---|
| Depositing User: | David Swan |
| URI: | https://sure.sunderland.ac.uk/id/eprint/16676 |
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