title: Enhanced activity of Akt in Teff cells from children with lupus nephritis is associated with reduced induction of tumor necrosis factor receptor-associated factor 6 and increased OX40 expression.
abstract: OBJECTIVE
  The breakdown of peripheral tolerance mechanisms is central to the pathogenesis of systemic lupus erythematosus (SLE). Although true Treg cells in patients with SLE exhibit intact suppressive activity, Teff cells are resistant to suppression. The underlying mechanisms are incompletely understood. This study was undertaken to examine the Akt signaling pathway and molecules that may alter its activity in T cells in lupus patients.
  
  
  METHODS
  The Akt pathway and its regulators were analyzed in Teff and Treg cells from children with lupus nephritis and controls using flow cytometry and real-time quantitative polymerase chain reaction. T cell proliferation was assessed by analysis of 5,6-carboxyfluorescein succinimidyl ester dilution.
  
  
  RESULTS
  CD4+CD45RA-FoxP3(low) and FoxP3- Teff cells from children with lupus nephritis expressed high levels of activated Akt, resulting in the down-regulation of the proapoptotic protein Bim and an enhanced proliferative response. The induction of tumor necrosis factor receptor-associated factor 6 (TRAF6) was impaired, and TRAF6 levels inversely correlated with Akt activity. Although the expression of OX40 was enhanced on Teff cells from children with lupus nephritis compared to controls, OX40 stimulation failed to significantly increase TRAF6 expression in cells from patients, in contrast to those from healthy controls, but resulted in further increased Akt activation that was reversed by blockade of OX40 signaling. Moreover, inhibition of Akt signaling markedly decreased the proliferation of Teff cells from lupus patients.
  
  
  CONCLUSIONS
  Our findings indicate that hyperactivation of the Akt pathway in Teff cells from children with lupus nephritis is associated with reduced induction of TRAF6 and up-regulation of OX40, which may cause Teff cell resistance to Treg cell-mediated suppression.
authors.affiliation: Innsbruck Medical University, Innsbruck, Austria.
authors.forename: Sudhir
authors.initials: S
authors.lastname: Kshirsagar
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Binder
authors.forename: Magdalena
authors.initials: M
authors.lastname: Riedl
authors.forename: Gottfried
authors.initials: G
authors.lastname: Wechselberger
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Steichen
authors.forename: Monika
authors.initials: M
authors.lastname: Edelbauer
mesh_terms: D000293:Adolescent; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D002455:Cell Division / Q000276:immunology; D002478:Cells, Cultured; D002648:Child; D005260:Female; D051858:Forkhead Transcription Factors / Q000378:metabolism; D006801:Humans; D017493:Leukocyte Common Antigens / Q000378:metabolism; D008181:Lupus Nephritis / Q000276:immunology / Q000378:metabolism*; D008297:Male; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D053262:Receptors, OX40 / Q000276:immunology / Q000378:metabolism*; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D048029:TNF Receptor-Associated Factor 6 / Q000276:immunology / Q000378:metabolism*; D015854:Up-Regulation / Q000276:immunology
chemical_list: C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D053262:Receptors, OX40; D048029:TNF Receptor-Associated Factor 6; C505716:TNFRSF4 protein, human; C494918:AKT1 protein, human; D051057:Proto-Oncogene Proteins c-akt; D017493:Leukocyte Common Antigens