Diagenode

Defective CD3gamma gene transcription is associated with NFATc2 overexpression in the lymphocytic variant of hypereosinophilic syndrome.


Willard-Gallo KE, Badran BM, Ravoet M, Zerghe A, Burny A, Martiat P, Goldman M, Roufosse F, Sibille C

OBJECTIVE: Determine the molecular defects underlying the CD3(-)CD4(+) T-cell phenotype and persistence of this clonal population in patients with hypereosinophilic syndrome. PATIENTS AND 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. CONCLUSION: 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.

Tags
Bioruptor
Chromatin Shearing
ChIP-qPCR

Share this article

Published
October, 2005

Source

Events

 See all events

Twitter feed

News

 See all news