Pudjohartono Maria Fransiska, Powell Kate, Barnes Eleanor, Klenerman Paul, Provine Nicholas M
Translational Gastroenterology and Liver Unit, University of Oxford, Oxford, United Kingdom.
Pandemic Sciences Institute, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.
PLoS Pathog. 2025 Aug 22;21(8):e1013432. doi: 10.1371/journal.ppat.1013432. eCollection 2025 Aug.
The COVID-19 pandemic response demonstrated the effectiveness of adenovirus vector vaccines in inducing protective cellular and antibody responses. However, we still lack mechanistic understanding of the factors regulating immunity induced by this platform, especially innate pathways. We utilized a human tonsil organoid model to study the regulation of adaptive responses to ChAdOx1 nCoV-19. Innate activation and cytokine release occurred within 24 hours and T and B cell activation and antigen-specific antibody secretion occurred during the ensuing 14-day culture. Among the immune cell populations, plasmacytoid dendritic cells (pDCs) exhibited the highest ChAdOx1 transduction levels. pDC-derived IFN-ɑ was critical for humoral responses, but production of antigen in pDCs was dispensable. Furthermore, IL-6 enhanced humoral responses in both IFN-ɑ-dependent and independent manners, indicating intricate signaling interplay. IFN-ɑ and IL-6 also regulated the function of vaccine-activated CD4+ T cells, including TFH. These data provide key insights into innate pathways regulating ChAdOx1-induced immunity and highlights the promise of this model for vaccine platform mechanistic studies.
新冠疫情应对措施证明了腺病毒载体疫苗在诱导保护性细胞和抗体反应方面的有效性。然而，我们仍缺乏对调节该平台诱导免疫的因素的机制理解，尤其是先天免疫途径。我们利用人扁桃体类器官模型来研究对ChAdOx1 nCoV-19适应性反应的调节。先天免疫激活和细胞因子释放在24小时内发生，T细胞和B细胞激活以及抗原特异性抗体分泌在随后的14天培养过程中发生。在免疫细胞群体中，浆细胞样树突状细胞（pDC）表现出最高的ChAdOx1转导水平。pDC衍生的IFN-α对体液反应至关重要，但pDC中抗原的产生并非必需。此外，IL-6以依赖IFN-α和不依赖IFN-α的方式增强体液反应，表明存在复杂的信号相互作用。IFN-α和IL-6还调节疫苗激活的CD4+ T细胞的功能，包括滤泡辅助性T细胞（TFH）。这些数据为调节ChAdOx1诱导免疫的先天免疫途径提供了关键见解，并突出了该模型在疫苗平台机制研究方面的前景。
