Chattopadhyay Shagnik, Hazra Sayantee, Biswas Biswajit, Goswami Ritobrata
Department of Bioscience and Biotechnology, Indian Institute of Technology Kharagpur, Kharagpur, India.
Eur J Immunol. 2025 Jul;55(7):e51752. doi: 10.1002/eji.202451752.
CD4+ T helper cells are involved in multiple biological processes ranging from pathogen clearance to immune tolerance. Differentiation of CD4+ T cells into varied subsets is dependent on transcription factors, cytokines, micronutrients, and epigenetic modifications. Here, we report the molecular mechanisms imparted by the homeobox transcription factor HOXB4 in modulating Th2 and Th9 cell differentiation. We found that Hoxb4 induction in T helper cells was TGF-β-dependent. In Th9 cells, HOXB4 overexpression significantly increased IL-9 secretion, while in Th2 cells, HOXB4 could alter only IL-10 secretion among other type 2 cytokines. Promoter activity analyses revealed that HOXB4 was able to transactivate the Il9 and Il10 proximal promoters, while the Il4 and Il13 promoters were differentially modulated. We observed that HOXB4 could physically interact with the transcription factor PU.1 but not GATA3, and directly bind PU.1 response element on the DNA in Th9 cells. The recruitment of HOXB4 was found to be significantly increased in regulatory regions including cECR and CNS1 (Il9 promoter). Collectively, our findings suggest that HOXB4 works downstream of the TGF-β signalling pathway, associates with PU.1, binds the regulatory regions, and distinctly regulates both Th2 and Th9 cell differentiation.
CD4+辅助性T细胞参与从病原体清除到免疫耐受的多种生物学过程。CD4+ T细胞分化为不同亚群取决于转录因子、细胞因子、微量营养素和表观遗传修饰。在此，我们报告同源盒转录因子HOXB4在调节Th2和Th9细胞分化中所赋予的分子机制。我们发现T辅助细胞中Hoxb4的诱导是TGF-β依赖性的。在Th9细胞中，HOXB4过表达显著增加IL-9分泌，而在Th2细胞中，HOXB4在其他2型细胞因子中仅能改变IL-10分泌。启动子活性分析表明，HOXB4能够反式激活Il9和Il10近端启动子，而Il4和Il13启动子受到不同调节。我们观察到HOXB4能与转录因子PU.1发生物理相互作用，但不与GATA3相互作用，并在Th9细胞中直接结合DNA上的PU.1反应元件。发现在包括cECR和CNS1（Il9启动子）的调控区域中HOXB4的募集显著增加。总体而言，我们的研究结果表明，HOXB4在TGF-β信号通路下游起作用，与PU.1相关联，结合调控区域，并分别调节Th2和Th9细胞分化。
