Defective CD3γ gene transcription is associated with NFATc2 overexpression in the lymphocytic variant of hypereosinophilic syndrome

• Published in: Experimental hematology 2005-10, Vol.33 (10), p.1147-1159
• Main Authors: Willard-Gallo, Karen E., Badran, Bassam M., Ravoet, Marie, Zerghe, Anne, Burny, Arsène, Martiat, Philippe, Goldman, Michel, Roufosse, Florence, Sibille, Catherine
• Format: Article
• Language: English
• ISSN: 0301-472X; 1873-2399
• DOI: 10.1016/j.exphem.2005.06.027

Determine the molecular defects underlying the CD3 −CD4 + T-cell phenotype and persistence of this clonal population in patients with hypereosinophilic syndrome. 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. We demonstrate that the CD3 −CD4 + T cells, characterized by a clonal TCRβ 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 CD3γ gene transcripts is responsible for the defect in TCR/CD3 surface expression. In addition, the level of NFATc2 binding to NFAT motifs in the CD3γ gene promoter was greatly increased in the abnormal T cells. Our studies indicate that CD3γ promoter activity can be positively influenced by NFATc1 plus NF-κB 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-κB gene expression. 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 CD3γ gene expression.