Nature2014-06-24 2:48 PM

Ascl2 在TFH功能中的一个作用 Transcription factor achaete-scute homologue 2 initiates follicular T-helper-cell development

论文摘要 

TFH (follicular T-helper) 细胞专门在生发中心 (B淋巴细胞的增殖、发育和成熟中所涉及的淋巴器官) 中帮助B细胞。转录因子Bcl6是TFH 细胞发育所必需的,但却被认为不会控制CXCR5上调或T-细胞向滤泡的迁移。这项研究显示,第二个转录因子Ascl2直接调控CXCR5上调和CCR7下调,对于TFH 细胞发育的启动和生发中心的反应至关重要。

Abstract 

In immune responses, activated T cells migrate to B-cell follicles and develop into follicular T-helper (TFH) cells, a recently identified subset of CD4+ T cells specialized in providing help to B lymphocytes in the induction of germinal centre. Although Bcl6 has been shown to be essential in TFH-cell function, it may not regulate the initial migration of T cells or the induction of the TFH program, as exemplified by C-X-C chemokine receptor type 5 (CXCR5) upregulation. Here we show that expression of achaete-scute homologue 2 (Ascl2)—a basic helix–loop–helix (bHLH) transcription factor—is selectively upregulated in TFH cells. Ectopic expression of Ascl2 upregulates CXCR5 but not Bcl6, and downregulates C-C chemokine receptor 7 (CCR7) expression in T cells in vitro, as well as accelerating T-cell migration to the follicles and TFH-cell development in vivo in mice. Genome-wide analysis indicates that Ascl2 directly regulates TFH-related genes whereas it inhibits expression of T-helper cell 1 (TH1) and TH17 signature genes. Acute deletion of Ascl2, as well as blockade of its function with the Id3 protein in CD4+ T cells, results in impaired TFH-cell development and germinal centre response. Conversely, mutation of Id, known to cause antibody-mediated autoimmunity, greatly enhances TFH-cell generation. Thus, Ascl2 directly initiates TFH-cell development.

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