title: Defective CD3gamma gene transcription is associated with NFATc2 overexpression in the lymphocytic variant of hypereosinophilic syndrome.
abstract: OBJECTIVE
  Determine the molecular defects underlying the CD3(-)CD4(+) T-cell phenotype and persistence of this clonal population in patients with hypereosinophilic syndrome.
  
  
  METHODS
  Patients in this study suffer from the lymphocytic variant of hypereosinophilic syndrome distinguished by a CD3(-)CD4(+) T-cell clone that overexpresses Th2 cytokines upon activation and thereby provokes the eosinophilia. Interleukin-2-dependent CD3(-)CD4(+) T-cell lines were derived from patient blood at various disease stages and used to investigate the molecular modifications correlated with their abnormal phenotype.
  
  
  RESULTS
  We demonstrate that the CD3(-)CD4(+) T cells, characterized by a clonal TCRbeta gene rearrangement, maintained the same immunophenotype over the 6-year period of our study, during which one patient progressed from premalignant disease to CD3(-)CD4(+) T-cell lymphoma. We show that a specific loss of CD3gamma gene transcripts is responsible for the defect in TCR/CD3 surface expression. In addition, the level of NFATc2 binding to NFAT motifs in the CD3gamma gene promoter was greatly increased in the abnormal T cells. Our studies indicate that CD3gamma promoter activity can be positively influenced by NFATc1 plus NF-kappaB p50 and negatively regulated by NFATc2 containing complexes. We show that in patients' CD3(-)CD4(+) T cells, an increase in nuclear NFATc2 occurs in parallel with a decrease in NFATc1 and NF-kappaB gene expression.
  
  
  CONCLUSIONS
  Hypereosinophilic syndrome joins the growing number of pathological conditions where a defect in surface expression and/or function of the TCR/CD3 complex results from altered regulation of CD3gamma gene expression.
authors.affiliation: Laboratory of Experimental Hematology, Institut Jules Bordet, Université Libre de Bruxelles (ULB), Brussels, Belgium. kwillard@ulb.ac.be
authors.forename: Karen E
authors.initials: KE
authors.lastname: Willard-Gallo
authors.forename: Bassam M
authors.initials: BM
authors.lastname: Badran
authors.forename: Marie
authors.initials: M
authors.lastname: Ravoet
authors.forename: Anne
authors.initials: A
authors.lastname: Zerghe
authors.forename: Arsène
authors.initials: A
authors.lastname: Burny
authors.forename: Philippe
authors.initials: P
authors.lastname: Martiat
authors.forename: Michel
authors.initials: M
authors.lastname: Goldman
authors.forename: Florence
authors.initials: F
authors.lastname: Roufosse
authors.forename: Catherine
authors.initials: C
authors.lastname: Sibille
mesh_terms: D000328:Adult; D017252:CD3 Complex / Q000096:biosynthesis* / Q000235:genetics; D002460:Cell Line; D016207:Cytokines / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics; D006801:Humans; D017681:Hypereosinophilic Syndrome / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016328:NF-kappa B / Q000378:metabolism; D050778:NFATC Transcription Factors / Q000235:genetics / Q000378:metabolism*; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000378:metabolism; D020218:Response Elements / Q000235:genetics; D018418:Th2 Cells / Q000378:metabolism* / Q000473:pathology; D014158:Transcription, Genetic / Q000235:genetics
chemical_list: D017252:CD3 Complex; C452842:CD3 antigen, gamma chain; D016207:Cytokines; D016328:NF-kappa B; D050778:NFATC Transcription Factors; C494006:NFATC2 protein, human; D011948:Receptors, Antigen, T-Cell