T-bet is a key regulator for the lineage commitment in CD4 T helper (Th) 1 cells by activating the hallmark production of interferon-c, and its expression level is linked to autoimmune, infectious, and allergic diseases.A T to C base substitution has been identified at position-1993 in the TBX21 (encoding T-bet) promoter and has been associated with asthma and systemic lupus erythematosus.This study aimed to investigate the molecular mechanisms responsible for the influence of the T-1993 C polymorphism on transcription and its functional effect by luciferase reporter, EMSAs, Chromatin immunoprecipitation assay, and flow cytometric analysis of intracellular T-bet, IFN-c and IL-4 expression in activated CD4+ T cells.The presence of a-1993T allele obviously increases promoter activity compared with that of a promoter with a-1993C allele.TBX21 promoter carrying-1993C allele possesses significantly stronger binding affinity to the Yin Yang 1 (YY1) transcription factor than that carrying -1993 T allele.YY1 overexpression decreased TBX21 promoter function in a T cell line, demonstrating that this element functions as a repressor.The C to T base exchange relieves the repression mediated by YY1.The individuals carrying-1993 C allele were determined to have significantly diminished expression of TBX21 and IFN-c and increased IL-4 production in cells compared with the individuals carrying-1993T allele (P < 0.05).These findings demonstrate that the TBX21 T-1993C polymorphism represses TBX21 expression and Thl cytokine production through control of YY1, which might result in the imbalance between Thl and Th2 immune responses in autoimmune or allergic diseases.