Tolerogenic dendritic cells generated with dexamethasone and vitamin D3 regulate rheumatoid arthritis CD4+T cells partly via transforming growth factor-β1.
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.
Musculoskeletal Research Group.|Arthritis Research UK Rheumatoid Arthritis Centre of Excellence (RACE).
A E
AE
Anderson
Musculoskeletal Research Group.
D J
DJ
Swan
Musculoskeletal Research Group.
O Y
OY
Wong
Musculoskeletal Research Group.
M
M
Buck
Musculoskeletal Research Group.|Arthritis Research UK Rheumatoid Arthritis Centre of Excellence (RACE).
O
O
Eltherington
Musculoskeletal Research Group.|Arthritis Research UK Rheumatoid Arthritis Centre of Excellence (RACE).
R A
RA
Harry
Musculoskeletal Research Group.
A M
AM
Patterson
Musculoskeletal Research Group.|Arthritis Research UK Rheumatoid Arthritis Centre of Excellence (RACE).
A G
AG
Pratt
Musculoskeletal Research Group.|Arthritis Research UK Rheumatoid Arthritis Centre of Excellence (RACE).
G
G
Reynolds
Musculoskeletal Research Group.
J-P
JP
Doran
Applied Immunobiology and Transplantation Research Group, Institute of Cellular Medicine at the Newcastle NIHR Biomedical Research Centre, Newcastle University and Newcastle upon Tyne NHS Trust, Newcastle upon Tyne, UK.
J A
JA
Kirby
Musculoskeletal Research Group.|Arthritis Research UK Rheumatoid Arthritis Centre of Excellence (RACE).
J D
JD
Isaacs
Musculoskeletal Research Group.|Arthritis Research UK Rheumatoid Arthritis Centre of Excellence (RACE).
C M U
CM
Hilkens
D001172:Arthritis, Rheumatoid / Q000276:immunology / Q000628:therapy*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002478:Cells, Cultured; D002762:Cholecalciferol / Q000494:pharmacology; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology* / Q000637:transplantation; D003907:Dexamethasone / Q000494:pharmacology; D051858:Forkhead Transcription Factors / Q000378:metabolism; D006801:Humans; D007108:Immune Tolerance; D056747:Immunomodulation; D007167:Immunotherapy / Q000379:methods*; D018664:Interleukin-12 / Q000235:genetics / Q000378:metabolism; D008213:Lymphocyte Activation; D051899:Smad2 Protein / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*
C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; C497782:SMAD2 protein, human; D051899:Smad2 Protein; D053773:Transforming Growth Factor beta1; D018664:Interleukin-12; D002762:Cholecalciferol; D003907:Dexamethasone
TGF-β1; regulation; rheumatoid arthritis; tolerogenic dendritic cells
J Immunol. 1989 Aug 15;143(4):1142-8
2663990
Clin Exp Immunol. 1996 Mar;103(3):357-67
8608632
Scand J Immunol. 1998 Sep;48(3):286-92
9743215
Rheumatology (Oxford). 1999 Nov;38(11):1058-67
10556256
Arthritis Res Ther. 2007;9(3):R59
17594488
Nat Rev Mol Cell Biol. 2007 Dec;8(12):970-82
18000526
Genes Dev. 2000 Jan 15;14(2):187-97
10652273
PeerJ. 2016 Aug 30;4:e2300
27635311
J Clin Immunol. 2008 Nov;28(6):640-6
18810612
J Leukoc Biol. 2009 Feb;85(2):243-50
18971286
J Autoimmun. 2012 Sep;39(3):222-8
22704962
Arthritis Res Ther. 2011 Jun 27;13(3):R106
21708033
J Clin Invest. 2001 Aug;108(4):601-9
11518734
Ann Rheum Dis. 2017 Jan;76(1):227-234
27117700
Ann Rheum Dis. 2010 Nov;69(11):2042-50
20551157
Arthritis Rheum. 2010 Dec;62(12):3656-65
20862679
J Exp Med. 1989 Jan 1;169(1):291-6
2909658
Clin Exp Immunol. 1990 Aug;81(2):278-85
2201470
J Leukoc Biol. 2008 Jul;84(1):124-33
18430785
Clin Exp Immunol. 2013 May;172(2):148-57
23574312
Gastroenterology. 2009 Apr;136(4):1308-16, e1-3
19192480
Acta Biochim Biophys Sin (Shanghai). 2009 Apr;41(4):263-72
19352540
Int Immunol. 1994 Mar;6(3):469-75
8186198
Clin Exp Immunol. 1991 Dec;86(3):380-6
1747946
J Biol Chem. 2000 Sep 29;275(39):30226-31
10903323
Clin Immunol Immunopathol. 1995 Aug;76(2):187-94
7614737
J Leukoc Biol. 2009 Jan;85(1):29-33
18818372
J Immunol. 2003 Oct 1;171(7):3855-62
14500687
Int Immunopharmacol. 2003 Feb;3(2):233-45
12586604
J Immunol. 2001 Jul 15;167(2):773-8
11441082
Arthritis Res Ther. 2004;6(2):R114-9
15059274
Lab Invest. 1994 May;70(5):620-30
8196359