Synovial CD4+ T-cell-derived GM-CSF supports the differentiation of an inflammatory dendritic cell population in rheumatoid arthritis

Ann Rheum Dis. 2016 May;75(5):899-907. doi: 10.1136/annrheumdis-2014-206578. Epub 2015 Apr 28.


Objective: A population of synovial inflammatory dendritic cells (infDCs) has recently been identified in rheumatoid arthritis (RA) and is thought to be monocyte-derived. Here, we investigated the role and source of granulocyte macrophage-colony-stimulating factor (GM-CSF) in the differentiation of synovial infDC in RA.

Methods: Production of GM-CSF by peripheral blood (PB) and synovial fluid (SF) CD4+ T cells was assessed by ELISA and flow cytometry. In vitro CD4+ T-cell polarisation experiments were performed with T-cell activating CD2/CD3/CD28-coated beads in the absence or presence of pro-Th1 or pro-Th17 cytokines. CD1c+ DC and CD16+ macrophage subsets were flow-sorted and analysed morphologically and functionally (T-cell stimulatory/polarising capacity).

Results: RA-SF CD4+ T cells produced abundant GM-CSF upon stimulation and significantly more than RA-SF mononuclear cells depleted of CD4+ T cells. GM-CSF-producing T cells were significantly increased in RA-SF compared with non-RA inflammatory arthritis SF, active RA PB and healthy donor PB. GM-CSF-producing CD4+ T cells were expanded by Th1-promoting but not Th17-promoting conditions. Following coculture with RA-SF CD4+ T cells, but not healthy donor PB CD4+ T cells, a subpopulation of monocytes differentiated into CD1c+ infDC; a process dependent on GM-CSF. These infDC displayed potent alloproliferative capacity and enhanced GM-CSF, interleukin-17 and interferon-γ production by CD4+ T cells. InfDC with an identical phenotype to in vitro generated cells were significantly enriched in RA-SF compared with non-RA-SF/tissue/PB.

Conclusions: We demonstrate a therapeutically tractable feedback loop of GM-CSF secreted by RA synovial CD4+ T cells promoting the differentiation of infDC with potent capacity to induce GM-CSF-producing CD4+ T cells.

Keywords: Autoimmunity; Cytokines; Inflammation; Rheumatoid Arthritis; T Cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antigens, CD1 / analysis
  • Arthritis, Rheumatoid / immunology*
  • CD4-Positive T-Lymphocytes / immunology*
  • Coculture Techniques
  • Cytokines / biosynthesis
  • Dendritic Cells / immunology*
  • Glycoproteins / analysis
  • Granulocyte-Macrophage Colony-Stimulating Factor / biosynthesis
  • Granulocyte-Macrophage Colony-Stimulating Factor / immunology*
  • Humans
  • Immunophenotyping
  • Lipopolysaccharide Receptors / analysis
  • Macrophages / immunology
  • Monocytes / immunology
  • Osteoarthritis / immunology
  • Synovial Fluid / immunology
  • Th1 Cells / immunology


  • Antigens, CD1
  • CD1C protein, human
  • Cytokines
  • Glycoproteins
  • Lipopolysaccharide Receptors
  • Granulocyte-Macrophage Colony-Stimulating Factor