title: Targeting CD1c-expressing classical dendritic cells to prevent thymus and activation-regulated chemokine (TARC)-mediated T-cell chemotaxis in rheumatoid arthritis.
abstract: OBJECTIVE
  Thymus and activation-regulated chemokine (TARC) attracts cells that express the C-C chemokine receptor type 4 (CCR4), including CD4 T cells. As expression of CCR4 is increased on peripheral T cells and intra-articular interleukin (IL)-17-producing cells in patients with rheumatoid arthritis (RA), we investigated whether TARC plays a role in the attraction of T cells to the synovial compartment. In addition, we assessed the role of classical dendritic cells (cDCs) in the production of TARC in RA.
  
  
  METHODS
  TARC was measured in synovial fluid (SF) samples from RA and osteoarthritis (OA) patients. Spontaneous and thymic stromal lymphopoietin (TSLP)-induced TARC production by mononuclear cells (MCs) and CD1c cDCs from peripheral blood (PB) and SF was assessed. The role of TARC in CD4 T-cell migration towards cDCs was assessed and the contribution of CD1c-expressing cells to TARC production was studied.
  
  
  RESULTS
  TARC concentrations were higher in SF of RA patients compared to OA patients. MCs from SF produced TARC spontaneously and produced more TARC upon stimulation than paired PBMCs. Blocking TARC strongly inhibited CD4 T-cell chemotaxis by TSLP-stimulated cDCs, associated with decreased production of tumour necrosis factor (TNF)-α. Depletion of cDCs from SFMCs strongly reduced TARC production.
  
  
  CONCLUSIONS
  TARC levels are increased in RA SF and our data indicate that this results from production by SFMCs and in particular CD1c cDCs. TARC attracts T cells and TARC secretion by MCs is crucially dependent on the presence of CD1c cDCs. Considering the potential of SF cDCs to activate T cells and induce pro-inflammatory cytokine secretion, targeting intra-articular cDCs constitutes a novel therapeutic approach in RA.
authors.affiliation: a Department of Rheumatology and Clinical Immunology , University Medical Centre Utrecht , The Netherlands.|b Laboratory of Translational Immunology , University Medical Centre Utrecht , The Netherlands.
authors.forename: M R
authors.initials: MR
authors.lastname: Hillen
authors.affiliation: a Department of Rheumatology and Clinical Immunology , University Medical Centre Utrecht , The Netherlands.|b Laboratory of Translational Immunology , University Medical Centre Utrecht , The Netherlands.
authors.forename: F M
authors.initials: FM
authors.lastname: Moret
authors.affiliation: a Department of Rheumatology and Clinical Immunology , University Medical Centre Utrecht , The Netherlands.
authors.forename: Kmg
authors.initials: K
authors.lastname: van der Wurff-Jacobs
authors.affiliation: a Department of Rheumatology and Clinical Immunology , University Medical Centre Utrecht , The Netherlands.|b Laboratory of Translational Immunology , University Medical Centre Utrecht , The Netherlands.
authors.forename: Trdj
authors.initials: T
authors.lastname: Radstake
authors.affiliation: a Department of Rheumatology and Clinical Immunology , University Medical Centre Utrecht , The Netherlands.|b Laboratory of Translational Immunology , University Medical Centre Utrecht , The Netherlands.
authors.forename: C E
authors.initials: CE
authors.lastname: Hack
authors.affiliation: a Department of Rheumatology and Clinical Immunology , University Medical Centre Utrecht , The Netherlands.
authors.forename: Fpjg
authors.initials: F
authors.lastname: Lafeber
authors.affiliation: a Department of Rheumatology and Clinical Immunology , University Medical Centre Utrecht , The Netherlands.|b Laboratory of Translational Immunology , University Medical Centre Utrecht , The Netherlands.
authors.forename: Jag
authors.initials: J
authors.lastname: van Roon
mesh_terms: D000328:Adult; D000368:Aged; D018949:Antigens, CD1 / Q000378:metabolism; D001172:Arthritis, Rheumatoid / Q000378:metabolism*; D015496:CD4-Positive T-Lymphocytes / Q000502:physiology*; D016022:Case-Control Studies; D002478:Cells, Cultured; D054414:Chemokine CCL17 / Q000378:metabolism*; D002633:Chemotaxis; D003713:Dendritic Cells / Q000502:physiology*; D005260:Female; D006023:Glycoproteins / Q000378:metabolism; D006801:Humans; D008297:Male; D008875:Middle Aged; D013582:Synovial Fluid / Q000378:metabolism*
chemical_list: D018949:Antigens, CD1; C106230:CCL17 protein, human; C437944:CD1C protein, human; D054414:Chemokine CCL17; D006023:Glycoproteins