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Transcription factor achaete-scute homologue 2 initiates follicular T-helper-cell development

2014; Nature Portfolio; Volume: 507; Issue: 7493 Linguagem: Inglês

10.1038/nature12910

1476-4687

Xindong Liu, Xin Chen, Bo Zhong, Aibo Wang, Xiaohu Wang, Fuliang Chu, Roza Nurieva, Xiaowei Yan, Ping Chen, Laurens G. van der Flier, Hiroko Nakatsukasa, Sattva S. Neelapu, Wanjun Chen, Hans Clevers, Qiang Tian, Hai Qi, Lai Wei, Chen Dong,

Immunotherapy and Immune Responses

Here, the helix–loop–helix transcription factor Ascl2 is shown to be critically important for the initiation of follicular T-helper-cell development and the germinal centre response. TFH (follicular T-helper) cells are specialized in helping B cells in the germinal centres — lymphoid organs involved in the proliferation, development and maturation of B lymphocytes. The transcription factor Bcl6 is required for TFH cell development but is thought not to control CXCR5 upregulation or T-cell migration to follicles. This study shows that a second transcription factor, Ascl2, directly regulates CXCR5 upregulation and CCR7 downregulation and is critically important for the initiation of TFH cell development and the germinal centre response. 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 centres1,2. Although Bcl6 has been shown to be essential in TFH-cell function, it may not regulate the initial migration of T cells3 or the induction of the TFH program, as exemplified by C-X-C chemokine receptor type 5 (CXCR5) upregulation4. Here we show that expression of achaete-scute homologue 2 (Ascl2)—a basic helix–loop–helix (bHLH) transcription factor5—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 Id3, known to cause antibody-mediated autoimmunity, greatly enhances TFH-cell generation. Thus, Ascl2 directly initiates TFH-cell development.