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

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 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 patientsʹ CD3−CD4+ T cells, an increase in nuclear NFATc2 occurs in parallel with a decrease in NFATc1 and NF-κB 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 CD3γ gene expression.