title: Reduced CD4+,CD25- T cell sensitivity to the suppressive function of CD4+,CD25high,CD127 -/low regulatory T cells in patients with active systemic lupus erythematosus.
abstract: OBJECTIVE
  CD4+,CD25high regulatory T (Treg) cells play a crucial role in the maintenance of self tolerance and prevention of organ-specific autoimmunity. The presence of many in vivo-preactivated CD4+,CD25++ T cells in patients with systemic lupus erythematosus (SLE) poses a difficulty in discriminating CD25++ activated T cells from CD25high Treg cells. To overcome this problem, we analyzed the phenotype and function of CD4+,CD25high,CD127(-/low) natural Treg (nTreg) cells isolated from the peripheral blood of patients with SLE.
  
  
  METHODS
  CD4+,CD25high,CD127(-/low) nTreg cells and CD4+,CD25- responder T (Tresp) cells from patients with SLE and normal donors were separated by fluorescence-activated cell sorting. Cell proliferation was quantified by 3H-thymidine incorporation, and immunophenotyping of the cells was done using FACScan.
  
  
  RESULTS
  Comparable percentages of CD4+,CD25high,FoxP3+ T cells were observed in patients with SLE and normal donors. Proliferation of SLE nTreg cells sorted into the subset CD4+,CD25high,CD127(-/low) was significantly decreased compared with that of SLE nTreg cells sorted into the subset CD4+,CD25high (mean +/- SEM 2,223 +/- 351 counts per minute versus 9,104 +/- 1,720 cpm, respectively), while in normal donors, these values were 802 +/- 177 cpm and 2,028 +/- 548 cpm, respectively, confirming that effector cell contamination was reduced. Notably, the suppressive activity of nTreg cells was intact in all groups. However, CD4+,CD25- Tresp cells isolated from patients with active SLE were significantly less sensitive than those from patients with inactive SLE to the suppressive function of autologous or normal donor CD4+,CD25high,CD127(-/low) nTreg cells. Furthermore, a significant inverse correlation was observed between the extent of T cell regulation in suppressor assays and the level of lupus disease activity.
  
  
  CONCLUSIONS
  This study is the first to show that, in human SLE, impaired sensitivity of Tresp cells to the suppressive effects of a comparably functional, highly purified nTreg cell population leads to a defective suppression of T cell proliferation in active SLE. Studies aiming to define the mechanisms leading to Tresp cell resistance might help in the development of highly specific, alternative immunotherapeutic tools for the control of systemic autoimmune diseases such as SLE.
authors.affiliation: University of Heidelberg, Heidelberg, Germany.
authors.forename: Ram Kumar Chowdary
authors.initials: RK
authors.lastname: Venigalla
authors.forename: Theresa
authors.initials: T
authors.lastname: Tretter
authors.forename: Stefan
authors.initials: S
authors.lastname: Krienke
authors.forename: Regina
authors.initials: R
authors.lastname: Max
authors.forename: Volker
authors.initials: V
authors.lastname: Eckstein
authors.forename: Norbert
authors.initials: N
authors.lastname: Blank
authors.forename: Christoph
authors.initials: C
authors.lastname: Fiehn
authors.forename: Anthony Dick
authors.initials: AD
authors.lastname: Ho
authors.forename: Hanns-Martin
authors.initials: HM
authors.lastname: Lorenz
mesh_terms: D000328:Adult; D000368:Aged; D015704:CD4 Antigens; D016022:Case-Control Studies; D049109:Cell Proliferation; D005260:Female; D051858:Forkhead Transcription Factors / Q000378:metabolism; D006801:Humans; D053645:Interleukin-2 Receptor alpha Subunit; D053699:Interleukin-7 Receptor alpha Subunit; D008180:Lupus Erythematosus, Systemic / Q000276:immunology* / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D012720:Severity of Illness Index; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
chemical_list: D015704:CD4 Antigens; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D053645:Interleukin-2 Receptor alpha Subunit; D053699:Interleukin-7 Receptor alpha Subunit