title: GATA-3 up-regulation in CD8+ T cells as a biomarker of immune dysfunction in systemic sclerosis, resulting in excessive interleukin-13 production.
abstract: OBJECTIVE
  Despite the importance of interleukin-13 (IL-13) in systemic sclerosis (SSc) and other fibrotic diseases, its mechanisms of action are not understood. We have reported that excessive amounts of IL-13 are produced by peripheral blood effector CD8+ T cells from patients with diffuse cutaneous SSc (dcSSc). The aim of the present study was to establish the molecular basis of IL-13 dysregulation in the pathogenesis of SSc.
  
  
  METHODS
  Quantitative polymerase chain reaction analysis and intracellular staining were used to study the transcription factors that control naive peripheral blood CD8+ T cell differentiation into type 1 and type 2 cytokine-secreting cells. Intracellular staining revealed that GATA-3 levels in freshly isolated naive CD8+ T cells correlated with specific clinical manifestations. We therefore assessed the effects of GATA-3 inhibition on IL-13 production in CD8+ T cells from the SSc patients.
  
  
  RESULTS
  Freshly isolated naive peripheral blood CD8+ T cells expressed high levels of GATA-3 and failed to down-regulate IL-13 production when cultured under type 1-skewing conditions, but maintained adequate levels of interferon-γ production. Cellular GATA-3 levels were significantly higher in patients with dcSSc and early inflammatory disease. Silencing of GATA-3 with small interfering RNA significantly reduced IL-13 production by CD8+ T cells, demonstrating a causal relationship between GATA-3 and IL-13.
  
  
  CONCLUSIONS
  These results provide important new insights into SSc pathogenesis and suggest that increased GATA-3 expression in CD8+ T cells could be a highly relevant biomarker of immune dysfunction in patients with dcSSc. GATA-3 could be a novel therapeutic target for this currently incurable disease.
authors.affiliation: Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, USA.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Medsger
authors.forename: Dana E
authors.initials: DE
authors.lastname: Ivanco
authors.forename: Lela
authors.initials: L
authors.lastname: Kardava
authors.forename: Penelope A
authors.initials: PA
authors.lastname: Morel
authors.forename: Mary R
authors.initials: MR
authors.lastname: Lucas
authors.forename: Patrizia
authors.initials: P
authors.lastname: Fuschiotti
mesh_terms: D000328:Adult; D015415:Biomarkers / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D015536:Down-Regulation; D005260:Female; D050990:GATA3 Transcription Factor / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis / Q000276:immunology; D018793:Interleukin-13 / Q000096:biosynthesis*; D008297:Male; D008875:Middle Aged; D034741:RNA, Small Interfering / Q000494:pharmacology; D045743:Scleroderma, Diffuse / Q000276:immunology; D015854:Up-Regulation
chemical_list: D015415:Biomarkers; D050990:GATA3 Transcription Factor; D018793:Interleukin-13; D034741:RNA, Small Interfering; D007371:Interferon-gamma