1Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Sci Signal. 2013 Dec 17;6(306):ra110. doi: 10.1126/scisignal.2004273.
The proto-oncogene c-Maf is a transcription factor that plays a critical role in the differentiation of various T helper (T(H)) cell subsets. The amount of c-Maf increases after stimulation of the T cell receptor (TCR), which results in the production of multiple cytokines. We showed that two essential regulators of the transcription factor nuclear factor κB (NF-κB), the scaffold protein CARMA1 and the kinase IKKβ [inhibitor of NF-κB (IκB) kinase β], are also critical for the activation of c-Maf. Although CARMA1 deficiency did not affect the TCR-dependent increase in c-Maf abundance in T cells, CARMA1-dependent activation of the IKK complex was required for the nuclear translocation of c-Maf and its binding to the promoters of its target genes. Consistent with a role for c-Maf in the development of T follicular helper (T(FH)) cells, which provide help to B cells in the germinal centers of the spleen, CARMA1- or IKKβ-deficient mice immunized with peptide antigen had defects in the generation of T(FH) cells, formation of germinal centers, and production of antigen-specific antibodies. Together, these data suggest a mechanism by which c-Maf is regulated during T cell activation and differentiation.
原癌基因 c-Maf 是一种转录因子，在各种辅助性 T 细胞（T(H)）亚群的分化中发挥关键作用。T 细胞受体（TCR）刺激后，c-Maf 的数量增加，导致多种细胞因子的产生。我们表明，转录因子核因子 κB（NF-κB）的两个重要调节因子，支架蛋白 CARMA1 和激酶 IKKβ[NF-κB（IκB）激酶β]，对于 c-Maf 的激活也是至关重要的。尽管 CARMA1 缺乏并不影响 TCR 依赖性 T 细胞中 c-Maf 丰度的增加，但 IKK 复合物的 CARMA1 依赖性激活对于 c-Maf 的核易位及其与靶基因启动子的结合是必需的。与 c-Maf 在滤泡辅助性 T（T(FH)）细胞发育中的作用一致，T(FH)细胞在脾脏生发中心为 B 细胞提供帮助，用肽抗原免疫的 CARMA1 或 IKKβ 缺陷小鼠在 T(FH)细胞的产生、生发中心的形成和抗原特异性抗体的产生方面存在缺陷。这些数据共同表明了一种在 T 细胞激活和分化过程中调节 c-Maf 的机制。
