Vice President´s Research Group 1: Molecular Allergology, Paul-Ehrlich-Institut, Langen, Germany.
Z6 Occupational Safety, Paul-Ehrlich-Institut, Langen, Germany.
Front Immunol. 2022 Aug 17;13:916491. doi: 10.3389/fimmu.2022.916491. eCollection 2022.
Recently, bacterial components were shown to enhance immune responses by shifting immune cell metabolism towards glycolysis and lactic acid production, also known as the Warburg Effect. Currently, the effect of allergen products for immunotherapy (AIT) and commercial vaccines on immune cell metabolism is mostly unknown.
To investigate the effect of AIT products (adjuvanted with either MPLA or Alum) on myeloid dendritic cell (mDC) metabolism and activation.
Bone marrow-derived mDCs were stimulated with five allergoid-based AIT products (one adjuvanted with MPLA, four adjuvanted with Alum) and two MPLA-adjuvanted vaccines and analyzed for their metabolic activation, expression of cell surface markers, and cytokine secretion by ELISA. mDCs were pre-incubated with either immunological or metabolic inhibitors or cultured in glucose- or glutamine-free culture media and subsequently stimulated with the MPLA-containing AIT product (AIT product 1). mDCs were co-cultured with allergen-specific CD4+ T cells to investigate the contribution of metabolic pathways to the T cell priming capacity of mDCs stimulated with AIT product 1.
Both the MPLA-containing AIT product 1 and commercial vaccines, but not the Alum-adjuvanted AIT products, activated Warburg metabolism and TNF-α secretion in mDCs. Further experiments focused on AIT product 1. Metabolic analysis showed that AIT product 1 increased glycolytic activity while also inducing the secretion of IL-1β, IL-10, IL-12, and TNF-α. Both rapamycin (mTOR-inhibitor) and SP600125 (SAP/JNK MAPK-inhibitor) dose-dependently suppressed the AIT product 1-induced Warburg Effect, glucose consumption, IL-10-, and TNF-α secretion. Moreover, both glucose- and glutamine deficiency suppressed secretion of all investigated cytokines (IL-1β, IL-10, and TNF-α). Glucose metabolism in mDCs was also critical for the (Th1-biased) T cell priming capacity of AIT product 1-stimulated mDCs, as inhibition of mTOR signaling abrogated their ability to induce Th1-responses.
The AIT product and commercial vaccines containing the adjuvant MPLA were shown to modulate the induction of immune responses by changing the metabolic state of mDCs. Better understanding the mechanisms underlying the interactions between cell metabolism and immune responses will allow us to further improve vaccine development and AIT.
最近，细菌成分通过将免疫细胞代谢转向糖酵解和乳酸生成（也称为沃伯格效应）来增强免疫反应，这已得到证实。目前，免疫疗法（AIT）产品和商业疫苗对免疫细胞代谢的影响在很大程度上尚不清楚。
研究 AIT 产品（用 MPLA 或 Alum 佐剂）对髓样树突状细胞（mDC）代谢和激活的影响。
用五种基于变应原的 AIT 产品（一种用 MPLA 佐剂，四种用 Alum 佐剂）和两种 MPLA 佐剂疫苗刺激骨髓来源的 mDC，并通过 ELISA 分析其代谢激活、细胞表面标志物表达和细胞因子分泌情况。用免疫或代谢抑制剂预先孵育 mDC，或在不含葡萄糖或谷氨酰胺的培养基中培养，然后用含 MPLA 的 AIT 产品（AIT 产品 1）刺激 mDC。将 mDC 与过敏原特异性 CD4+T 细胞共培养，以研究代谢途径对 AIT 产品 1 刺激的 mDC 引发 T 细胞的能力的贡献。
含 MPLA 的 AIT 产品 1 和商业疫苗均可激活 mDC 的沃伯格代谢和 TNF-α 分泌，但 Alum 佐剂的 AIT 产品无此作用。进一步的实验集中在 AIT 产品 1 上。代谢分析表明，AIT 产品 1 增加了糖酵解活性，同时也诱导了 IL-1β、IL-10、IL-12 和 TNF-α 的分泌。雷帕霉素（mTOR 抑制剂）和 SP600125（SAP/JNK MAPK 抑制剂）均呈剂量依赖性抑制 AIT 产品 1 诱导的沃伯格效应、葡萄糖消耗、IL-10 和 TNF-α 分泌。此外，葡萄糖和谷氨酰胺缺乏均抑制所有检测细胞因子（IL-1β、IL-10 和 TNF-α）的分泌。mDC 中的葡萄糖代谢对于 AIT 产品 1 刺激的 mDC 的（Th1 偏向）T 细胞启动能力也很关键，因为抑制 mTOR 信号会破坏其诱导 Th1 反应的能力。
含佐剂 MPLA 的 AIT 产品和商业疫苗被证明可以通过改变 mDC 的代谢状态来调节免疫反应的诱导。更好地了解细胞代谢和免疫反应之间相互作用的机制将使我们能够进一步改进疫苗开发和 AIT。
