Department of Microbiology Cancer Biology and Immunology, University of Virginia, Charlottesville, VA 22903, USA; Carter Immunology Center and UVA Cancer Center, University of Virginia, Charlottesville, VA 22903, USA.
Department of Biomedical Engineering, University of Virginia School of Engineering and Applied Sciences, Charlottesville, VA 22904, USA.
Cytokine. 2024 Nov;183:156731. doi: 10.1016/j.cyto.2024.156731. Epub 2024 Aug 20.
Subunit vaccines drive immune cell-cell interactions in the lymph node (LN), yet it remains unclear how distinct adjuvants influence the chemokines responsible for this interaction in the tissue. Here, we tested the hypothesis that classic Th1-polarizing vaccines elicit a unique chemokine signature in the LN compared to other adjuvants. Polyinosinic:polycytidylic acid (Poly I:C) vaccination resulted in dynamic upregulation of CXCL9 that was localized in the interfollicular region, a response not observed after vaccination with alum or a combination of alum and poly I:C. Experiments using in vivo mouse models and live ex vivo LN slices revealed that poly I:C vaccination resulted in a type-I IFN response in the LN that led to the secretion of IFNγ, and type-I IFN and IFNγ were required for CXCL9 expression in this context. CXCL9 expression in the LN was correlated with an IgG2c antibody polarization after vaccination; however, genetic depletion of the receptor for CXCL9 did not prevent the development of this polarization. Additionally, we measured secretion of CXCL9 from ex vivo LN slices after stimulation with a variety of adjuvants and confirmed that adjuvants that induced IFNγ responses also promoted CXCL9 expression. Taken together, these results identify a CXCL9 signature in a suite of Th1-polarizing adjuvants and determined the pathway involved in driving CXCL9 in the LN, opening avenues to target this chemokine pathway in future vaccines.
亚单位疫苗可在淋巴结 (LN) 中驱动免疫细胞间的相互作用，但目前尚不清楚不同佐剂如何影响组织中负责这种相互作用的趋化因子。在这里，我们检验了这样一个假设，即经典的 Th1 极化疫苗在 LN 中引发独特的趋化因子特征，与其他佐剂相比。聚肌苷酸：聚胞苷酸（Poly I:C）疫苗接种导致 CXCL9 的动态上调，该上调定位于滤泡间区域，而在用明矾或明矾和 Poly I:C 的组合接种后未观察到这种反应。使用体内小鼠模型和活的体外 LN 切片的实验表明，Poly I:C 疫苗接种在 LN 中引发 I 型 IFN 反应，导致 IFNγ的分泌，并且在这种情况下，I 型 IFN 和 IFNγ是 CXCL9 表达所必需的。LN 中 CXCL9 的表达与疫苗接种后的 IgG2c 抗体极化相关；然而，CXCL9 受体的基因缺失并没有阻止这种极化的发展。此外，我们测量了用各种佐剂刺激后的体外 LN 切片中 CXCL9 的分泌，并证实了诱导 IFNγ 反应的佐剂也促进了 CXCL9 的表达。总之，这些结果确定了 Th1 极化佐剂中 CXCL9 特征，并确定了在 LN 中驱动 CXCL9 的途径，为未来疫苗中靶向该趋化因子途径开辟了途径。
