title: Proinflammatory mediator-induced reversal of CD4+,CD25+ regulatory T cell-mediated suppression in rheumatoid arthritis.
abstract: OBJECTIVE
  We previously demonstrated that CD4+,CD25+ regulatory T (Treg) cells are present in increased numbers in the synovial fluid (SF) of rheumatoid arthritis (RA) patients and display enhanced suppressive activity as compared with their peripheral blood (PB) counterparts. Despite the presence of these immunoregulatory cells in RA, chronic inflammation persists. The purpose of the present study was to investigate whether particular proinflammatory mediators that are associated with RA could abrogate CD4+,CD25+ Treg-mediated suppression.
  
  
  METHODS
  Monocyte phenotype was determined by flow cytometry and cytokine levels by enzyme-linked immunosorbent assay. Magnetically sorted CD4+,CD25- and CD4+,CD25+ T cells derived from the PB and SF obtained from RA patients were stimulated alone or in coculture with anti-CD3 monoclonal antibody (mAb) and autologous antigen-presenting cells, in the absence or presence of anti-CD28 mAb or the proinflammatory cytokines interleukin-6 (IL-6), tumor necrosis factor alpha (TNFalpha), or IL-7.
  
  
  RESULTS
  Monocytes from the SF of RA patients displayed increased expression of HLA class II molecules, CD80, CD86, and CD40 as compared with PB-derived monocytes, indicating their activated status. Mimicking this increased costimulatory potential, addition of anti-CD28 mAb to cocultures of CD4+,CD25- and CD4+,CD25+ T cells resulted in reduced CD4+,CD25+ Treg-mediated suppression in both PB and SF. Furthermore, IL-7 and, to a limited extent, TNFalpha, both of which are produced by activated monocytes and were detected in SF, abrogated the CD4+,CD25+ Treg-mediated suppression. In contrast, IL-6 did not influence Treg-mediated suppression.
  
  
  CONCLUSIONS
  Our findings suggest that the interaction of CD4+,CD25+ Treg cells with activated monocytes in the joint might lead to diminished suppressive activity of CD4+,CD25+ Treg cells in vivo, thus contributing to the chronic inflammation in RA.
authors.affiliation: University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Jocea M R
authors.initials: JM
authors.lastname: van Amelsfort
authors.forename: Joel A G
authors.initials: JA
authors.lastname: van Roon
authors.forename: Madelon
authors.initials: M
authors.lastname: Noordegraaf
authors.forename: Kim M G
authors.initials: KM
authors.lastname: Jacobs
authors.forename: Johannes W J
authors.initials: JW
authors.lastname: Bijlsma
authors.forename: Floris P J G
authors.initials: FP
authors.lastname: Lafeber
authors.forename: Leonie S
authors.initials: LS
authors.lastname: Taams
mesh_terms: D000328:Adult; D000368:Aged; D001172:Arthritis, Rheumatoid / Q000276:immunology* / Q000503:physiopathology; D015551:Autoimmunity / Q000502:physiology; D051927:CD24 Antigen / Q000502:physiology*; D049109:Cell Proliferation; D016207:Cytokines / Q000502:physiology*; D005260:Female; D006801:Humans; D053645:Interleukin-2 Receptor alpha Subunit / Q000502:physiology*; D015851:Interleukin-7 / Q000235:genetics / Q000502:physiology; D008297:Male; D008875:Middle Aged; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000502:physiology
chemical_list: D051927:CD24 Antigen; D016207:Cytokines; D053645:Interleukin-2 Receptor alpha Subunit; D015851:Interleukin-7; D014409:Tumor Necrosis Factor-alpha