title: Dysfunctional CD4+,CD25+ regulatory T cells in untreated active systemic lupus erythematosus secondary to interferon-alpha-producing antigen-presenting cells.
abstract: OBJECTIVE
  To explore whether there are extrinsic factors that impair the suppressive function of CD4+,CD25+ regulatory T cells in patients with untreated active systemic lupus erythematosus (SLE).
  
  
  METHODS
  We studied 15 patients with untreated active SLE, 10 patients with SLE in remission, and 15 healthy control subjects. Percentages of CD4+,CD25+,FoxP3+ Treg cells and levels of forkhead box P3 (FoxP3) protein were analyzed by flow cytometry. Expression of messenger RNA (mRNA) for FoxP3 in purified Treg cell populations was assessed by real-time polymerase chain reaction analysis. Experiments examining Treg cell function in SLE were designed to distinguish primary from secondary T cell dysfunction. Levels of interferon-alpha (IFNalpha) in supernatants from the function assays were determined with an IFN-stimulated response element-luciferase reporter assay.
  
  
  RESULTS
  The percentage of CD4+,CD25+, FoxP3+ cells in peripheral blood was significantly increased in SLE patients as compared with controls (mean +/- SEM 9.11 +/- 0.73% versus 4.78 +/- 0.43%; P < 0.0001). We found no difference in FoxP3 expression at either the mRNA or protein level in any CD4+,CD25+ T cell subset from SLE patients as compared with controls. Antigen-presenting cells (APCs) from SLE patients were responsible for decreased Treg cell activity and could also render dysfunctional Treg cells from healthy control subjects. CD4+,CD25+ Treg cells from SLE patients exhibited normal suppressive activity when cultured with APCs from healthy controls. A partial Treg cell blockade effect was induced by the high levels of IFNalpha derived from SLE patient APCs.
  
  
  CONCLUSIONS
  We suggest that blockade of Treg cell-mediated suppression by IFNalpha-producing APCs in SLE patients may contribute to a pathogenic loss of peripheral tolerance in this disease.
authors.affiliation: Joint Molecular Rheumatology Laboratory of Renji Hospital, Shanghai JiaoTong University School of Medicine and Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Shanghai, China.
authors.forename: Bing
authors.initials: B
authors.lastname: Yan
authors.forename: Shuang
authors.initials: S
authors.lastname: Ye
authors.forename: Guangjie
authors.initials: G
authors.lastname: Chen
authors.forename: Miao
authors.initials: M
authors.lastname: Kuang
authors.forename: Nan
authors.initials: N
authors.lastname: Shen
authors.forename: Shunle
authors.initials: S
authors.lastname: Chen
mesh_terms: D000293:Adolescent; D000328:Adult; D000938:Antigen-Presenting Cells / Q000378:metabolism* / Q000473:pathology; D015704:CD4 Antigens / Q000378:metabolism*; D016022:Case-Control Studies; D005260:Female; D051858:Forkhead Transcription Factors / Q000378:metabolism; D006801:Humans; D016898:Interferon-alpha / Q000378:metabolism*; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism*; D008180:Lupus Erythematosus, Systemic / Q000378:metabolism* / Q000473:pathology; D008875:Middle Aged; D012333:RNA, Messenger / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000378:metabolism / Q000473:pathology; D013601:T-Lymphocytes / Q000378:metabolism* / Q000473:pathology; D050378:T-Lymphocytes, Regulatory / Q000378:metabolism / Q000473:pathology
chemical_list: D015704:CD4 Antigens; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D016898:Interferon-alpha; D053645:Interleukin-2 Receptor alpha Subunit; D012333:RNA, Messenger