Defective CD3gamma 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.


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.


CONCLUSIONS
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.
Willard-Gallo
Karen E
KE
Laboratory of Experimental Hematology, Institut Jules Bordet, Université Libre de Bruxelles (ULB), Brussels, Belgium. kwillard@ulb.ac.be
Badran
Bassam M
BM
Ravoet
Marie
M
Zerghe
Anne
A
Burny
Arsène
A
Martiat
Philippe
P
Goldman
Michel
M
Roufosse
Florence
F
Sibille
Catherine
C
D000328:Adult; D017252:CD3 Complex / Q000096:biosynthesis* / Q000235:genetics; D002460:Cell Line; D016207:Cytokines / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics; D006801:Humans; D017681:Hypereosinophilic Syndrome / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016328:NF-kappa B / Q000378:metabolism; D050778:NFATC Transcription Factors / Q000235:genetics / Q000378:metabolism*; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000378:metabolism; D020218:Response Elements / Q000235:genetics; D018418:Th2 Cells / Q000378:metabolism* / Q000473:pathology; D014158:Transcription, Genetic / Q000235:genetics
D017252:CD3 Complex; C452842:CD3 antigen, gamma chain; D016207:Cytokines; D016328:NF-kappa B; D050778:NFATC Transcription Factors; C494006:NFATC2 protein, human; D011948:Receptors, Antigen, T-Cell