title: A pivotal role for antigen-presenting cells overexpressing SOCS3 in controlling invariant NKT cell responses during collagen-induced arthritis.
abstract: OBJECTIVE
  Suppressor of cytokine signalling (SOCS) proteins constitute a class of intracellular proteins that are key physiological regulators of immune cell function. It has previously been shown that antigen-presenting cells (APCs) overexpressing SOCS3 steer T helper immune responses and protect against experimental arthritis. A study was undertaken to investigate the contribution of SOCS3 in regulating invariant natural killer T (iNKT) cell responses during collagen-induced arthritis (CIA).
  
  
  METHODS
  DBA/1 mice were immunised with type II collagen and adenoviruses encoding SOCS3 were administered intravenously before the clinical onset of arthritis. Murine APCs overexpressing SOCS3 were co-cultured with an iNKT cell hybridoma and interleukin 2 (IL-2) release was measured by Luminex multi-analyte technology. The frequency and activation of primary iNKT cells was assessed by flow cytometry. Murine APCs were analysed for cytokine and CD1d expression following viral SOCS3 gene transfer.
  
  
  RESULTS
  Viral overexpression of SOCS3 in APCs resulted in reduced activation of the iNKT cell hybridoma. Importantly, during initiation of CIA, adenovirus-mediated overexpression of SOCS3 in hepatic and splenic APCs inhibited iNKT cell expansion in both organs. The iNKT cell population from SOCS3-treated mice showed low expression of the early activation marker CD69 and primary liver iNKT cells produced less interferon γ and IL-4 upon α-galactosylceramide stimulation. No differences in CD1d surface expression were observed, but SOCS3-transduced APCs produced decreased levels of proinflammatory cytokines and increased levels of IL-10.
  
  
  CONCLUSIONS
  These results demonstrate a critical role for SOCS3 in controlling the immunostimulatory capacities of APCs, which has direct implications for the effector function of iNKT cells during arthritis.
authors.affiliation: Department of Rheumatology, Rheumatology Research and Advanced Therapeutics, Radboud University Nijmegen Medical Centre, The Netherlands.
authors.forename: Sharon
authors.initials: S
authors.lastname: Veenbergen
authors.forename: Miranda B
authors.initials: MB
authors.lastname: Bennink
authors.forename: Alsya J
authors.initials: AJ
authors.lastname: Affandi
authors.forename: Natacha
authors.initials: N
authors.lastname: Bessis
authors.forename: Jérôme
authors.initials: J
authors.lastname: Biton
authors.forename: Onno J
authors.initials: OJ
authors.lastname: Arntz
authors.forename: Wim B
authors.initials: WB
authors.lastname: van den Berg
authors.forename: Fons A J
authors.initials: FA
authors.lastname: van de Loo
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology*; D055610:Antigens, CD1d / Q000378:metabolism; D001169:Arthritis, Experimental / Q000276:immunology* / Q000517:prevention & control; D002478:Cells, Cultured; D016207:Cytokines / Q000276:immunology; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors; D008099:Liver / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology; D008264:Macrophages / Q000276:immunology; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D055611:Natural Killer T-Cells / Q000276:immunology*; D013154:Spleen / Q000276:immunology; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000097:blood* / Q000235:genetics
chemical_list: D055610:Antigens, CD1d; C526879:Cd1d1 protein, mouse; D016207:Cytokines; C491411:Socs3 protein, mouse; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins