Defective CD3gamma 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
• Subjects: Adult; CD3 Complex - biosynthesis; CD3 Complex - genetics; Cell Line; Cytokines - metabolism; Female; Gene Expression Regulation - genetics; Humans; Hypereosinophilic Syndrome - genetics; Hypereosinophilic Syndrome - metabolism; Hypereosinophilic Syndrome - pathology; NF-kappa B - metabolism; NFATC Transcription Factors - genetics; NFATC Transcription Factors - metabolism; Receptors, Antigen, T-Cell - genetics; Receptors, Antigen, T-Cell - metabolism; Response Elements - genetics; Th2 Cells - metabolism; Th2 Cells - pathology; Transcription, Genetic - genetics
• ISSN: 0301-472X

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 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. 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.