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A Thpok-Directed Transcriptional Circuitry Promotes Bcl6 and Maf Expression to Orchestrate T Follicular Helper Differentiation.
Immunity ( IF 25.5 ) Pub Date : 2019-08-15 , DOI: 10.1016/j.immuni.2019.06.023 Melanie S Vacchio 1 , Thomas Ciucci 1 , Yayi Gao 1 , Masashi Watanabe 2 , Mariah Balmaceno-Criss 1 , Mitchell T McGinty 1 , Allan Huang 1 , Qi Xiao 1 , Cameron McConkey 1 , Yongmei Zhao 3 , Jyoti Shetty 3 , Bao Tran 3 , Marion Pepper 4 , Golnaz Vahedi 5 , Marc K Jenkins 6 , Dorian B McGavern 7 , Rémy Bosselut 1
Immunity ( IF 25.5 ) Pub Date : 2019-08-15 , DOI: 10.1016/j.immuni.2019.06.023 Melanie S Vacchio 1 , Thomas Ciucci 1 , Yayi Gao 1 , Masashi Watanabe 2 , Mariah Balmaceno-Criss 1 , Mitchell T McGinty 1 , Allan Huang 1 , Qi Xiao 1 , Cameron McConkey 1 , Yongmei Zhao 3 , Jyoti Shetty 3 , Bao Tran 3 , Marion Pepper 4 , Golnaz Vahedi 5 , Marc K Jenkins 6 , Dorian B McGavern 7 , Rémy Bosselut 1
Affiliation
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The generation of high-affinity neutralizing antibodies, the objective of most vaccine strategies, occurs in B cells within germinal centers (GCs) and requires rate-limiting "help" from follicular helper CD4+ T (Tfh) cells. Although Tfh differentiation is an attribute of MHC II-restricted CD4+ T cells, the transcription factors driving Tfh differentiation, notably Bcl6, are not restricted to CD4+ T cells. Here, we identified a requirement for the CD4+-specific transcription factor Thpok during Tfh cell differentiation, GC formation, and antibody maturation. Thpok promoted Bcl6 expression and bound to a Thpok-responsive region in the first intron of Bcl6. Thpok also promoted the expression of Bcl6-independent genes, including the transcription factor Maf, which cooperated with Bcl6 to mediate the effect of Thpok on Tfh cell differentiation. Our findings identify a transcriptional program that links the CD4+ lineage with Tfh differentiation, a limiting factor for efficient B cell responses, and suggest avenues to optimize vaccine generation.
中文翻译：
Thpok定向转录电路促进Bcl6和Maf表达，以协调T滤泡辅助细胞的分化。
高亲和力中和抗体的产生是大多数疫苗策略的目标，发生在生发中心（GC）内的B细胞中，需要卵泡辅助CD4 + T（Tfh）细胞进行限速“帮助”。尽管Tfh分化是MHC II限制的CD4 + T细胞的属性，但驱动Tfh分化的转录因子（尤其是Bcl6）并不限于CD4 + T细胞。在这里，我们确定了在Tfh细胞分化，GC形成和抗体成熟过程中对CD4 +特异性转录因子Thpok的需求。Thpok促进了Bcl6的表达并与Bcl6的第一个内含子中的Thpok反应区域结合。Thpok还促进了Bcl6独立基因的表达，包括转录因子Maf，与Bcl6协同介导Thpok对Tfh细胞分化的影响。我们的发现确定了一个转录程序，该程序将CD4 +谱系与Tfh分化相联系，而Tfh分化是有效B细胞应答的限制因素，并提出了优化疫苗生成的途径。
更新日期：2019-08-15
中文翻译：
Thpok定向转录电路促进Bcl6和Maf表达，以协调T滤泡辅助细胞的分化。
高亲和力中和抗体的产生是大多数疫苗策略的目标，发生在生发中心（GC）内的B细胞中，需要卵泡辅助CD4 + T（Tfh）细胞进行限速“帮助”。尽管Tfh分化是MHC II限制的CD4 + T细胞的属性，但驱动Tfh分化的转录因子（尤其是Bcl6）并不限于CD4 + T细胞。在这里，我们确定了在Tfh细胞分化，GC形成和抗体成熟过程中对CD4 +特异性转录因子Thpok的需求。Thpok促进了Bcl6的表达并与Bcl6的第一个内含子中的Thpok反应区域结合。Thpok还促进了Bcl6独立基因的表达，包括转录因子Maf，与Bcl6协同介导Thpok对Tfh细胞分化的影响。我们的发现确定了一个转录程序，该程序将CD4 +谱系与Tfh分化相联系，而Tfh分化是有效B细胞应答的限制因素，并提出了优化疫苗生成的途径。
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