Huan Chongmin, Kelly Matthew L, Steele Ryan, Shapira Iuliana, Gottesman Susan R S, Roman Christopher A J
Program in Molecular and Cellular Biology, The School of Graduate Studies, State University of New York, Downstate Medical Center at Brooklyn, New York, New York 11203, USA.
Nat Immunol. 2006 Oct;7(10):1082-91. doi: 10.1038/ni1378. Epub 2006 Aug 27.
TFE3 and TFEB are broadly expressed transcription factors related to the transcription factor Mitf. Although they have been linked to cytokine signaling pathways in nonlymphoid cells, their function in T cells is unknown. TFE3-deficient mice are phenotypically normal, whereas TFEB deficiency causes early embryonic death. We now show that combined inactivation of TFE3 and TFEB in T cells resulted in a hyper-immunoglobulin M syndrome due to impaired expression of CD40 ligand by CD4(+) T cells. Native TFE3 and TFEB bound to multiple cognate sites in the promoter of the gene encoding CD40 ligand (Cd40lg), and maximum Cd40lg promoter activity and gene expression required TFE3 or TFEB. Thus, TFE3 and TFEB are direct, physiological and mutually redundant activators of Cd40lg expression in activated CD4(+) T cells critical for T cell-dependent antibody responses.
TFE3和TFEB是与转录因子Mitf相关的广泛表达的转录因子。尽管它们已与非淋巴细胞中的细胞因子信号通路相关联，但其在T细胞中的功能尚不清楚。TFE3缺陷型小鼠在表型上是正常的，而TFEB缺陷会导致早期胚胎死亡。我们现在表明，T细胞中TFE3和TFEB的联合失活会导致高免疫球蛋白M综合征，这是由于CD4(+) T细胞中CD40配体的表达受损所致。天然的TFE3和TFEB与编码CD40配体（Cd40lg）的基因启动子中的多个同源位点结合，并且最大的Cd40lg启动子活性和基因表达需要TFE3或TFEB。因此，TFE3和TFEB是活化的CD4(+) T细胞中Cd40lg表达的直接、生理且相互冗余的激活因子，对T细胞依赖性抗体反应至关重要。
