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.

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.

• Authors: Karen E Willard-Gallo, Bassam M Badran, Marie Ravoet, Anne Zerghe, Arsène Burny, Philippe Martiat, Michel Goldman, Florence Roufosse, Catherine Sibille
• Journal: Experimental hematology (Exp Hematol) Vol. 33 Issue 10 Pg. 1147-59 (Oct 2005) ISSN: 0301-472X [Print] Netherlands
• PMID: 16219537 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• CD3 Complex
• CD3 antigen, gamma chain
• Cytokines
• NF-kappa B
• NFATC Transcription Factors
• NFATC2 protein, human
• Receptors, Antigen, T-Cell

Topics

• Adult
• CD3 Complex (biosynthesis, genetics)
• Cell Line
• Cytokines (metabolism)
• Female
• Gene Expression Regulation (genetics)
• Humans
• Hypereosinophilic Syndrome (genetics, metabolism, pathology)
• NF-kappa B (metabolism)
• NFATC Transcription Factors (genetics, metabolism)
• Receptors, Antigen, T-Cell (genetics, metabolism)
• Response Elements (genetics)
• Th2 Cells (metabolism, pathology)
• Transcription, Genetic (genetics)