The functional role of C-terminal binding protein (CtBP)1, a transcriptional corepressor, in Th1 and Th2 cytokine expression in human T cells was investigated. Upon introduction of CtBP1 by lentiviral transduction system, IL-4 synthesis was suppressed but IFN-gamma was weakly up-regulated in human CD4(+) T cells. In contrast, a reduction of endogenously expressed CtBP1 in Jurkat T cells using RNAi technology selectively augmented IL-4 expression. The down-regulation of IL-4 by CtBP1 was achieved at the level of gene transcription. Deletion mutation analysis revealed that N-terminal similar to 200 amino acid and C-terminal similar to 50 amino acid residues are participated in CtBP1-mediated suppression of IL-4 expression. CtBP1 expressed in human CD4(+) T cells crucially contribute to Th1/Th2 differentiation via selective down-regulation of IL-4 synthesis. (C) 2009 Elsevier Inc. All rights reserved.