T-bet is a key regulator for the lineage commitment in CD4+ T helper (Th) 1 cells by activating the hallmark production of interferon-γ.Previously,two single nucleotide polymorphisms (SNPs) in the TBX21 promoter,T-1993C and T-1514C,have been shown by statistic studies to associate with systemic lupus erythematosus (SLE).The effect of-1993 SNP on the Yin Yang 1 transcription factormediated promoter activity has been already indicated.This study aimed to investigate roles of the T-1514C SNP on TBX21 transcription and its functional effect by luciferase reporter,electrophoretic mobility shift assay (EMSA),chromatin immunoprecipitation (ChIP) assay,and flow cytometric analysis of intraceilular T-bet,IFN-γ,and IL-4expression in activated CD4+ T cells.The TBX21 promoter carrying-1514C possessed significantly lower transcriptional activity than that of-1514T and was markedly downregulated by the overexpression of upstream stimulatory factor 1 (USF-1) when compared with the promoter carrying -1514T.EMSA indicated that the transcription factor U SF1 was bound to the-1514C allele probe with the affinity higher than that to the-1514T allele probe.ChIP assay suggested that USF-1 bound around-1514 of TBX21 genomic DNA in vivo in the human T cell line Jurkat with -1514C/T.The individuals carrying-1514C allele were determined to have significantly diminished expression of T-bet and IFN-γ and increased IL-4 production in CD4+ T cells compared with those of-1514T allele.The findings demonstrate that the T-1514C polymorphism affects TBX21 gene expression and Thl cytokine production by binding USF-1 to the SNP site.