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INTRODUCTION

Adjuvants added to subunit vaccines augment antigen-specific immune responses. One mechanism of adjuvant action is activation of pattern recognition receptors (PRRs) on innate immune cells. colonization factor A (BcfA); an outer membrane protein with adjuvant function, activates T1/T17-polarized immune responses to protein antigens from and SARS CoV-2. Unlike other adjuvants, BcfA does not elicit a T2 response.

METHODS

To understand the mechanism of BcfA-driven T1/T17 vs. T2 activation, we screened PRRs to identify pathways activated by BcfA. We then tested the role of this receptor in the BcfA-mediated activation of bone marrow-derived dendritic cells (BMDCs) using mice with germline deletion of TLR4 to quantify upregulation of costimulatory molecule expression and cytokine production in vitro and in vivo. Activity was also tested on human PBMCs.

RESULTS

PRR screening showed that BcfA activates antigen presenting cells through murine TLR4. BcfA-treated WT BMDCs upregulated expression of the costimulatory molecules CD40, CD80, and CD86 and produced IL-6, IL-12/23 p40, and TNF-α while TLR4 KO BMDCs were not activated. Furthermore, human PBMCs stimulated with BcfA produced IL-6. BcfA-stimulated murine BMDCs also exhibited increased uptake of the antigen DQ-OVA, supporting a role for BcfA in improving antigen presentation to T cells. BcfA further activated APCs in murine lungs. Using an T cell polarization system, we found that BcfA-stimulated BMDC supernatant supported T and T1 while suppressing T2 gene programming.

CONCLUSIONS

Overall, these data provide mechanistic understanding of how this novel adjuvant activates immune responses.

INTRODUCTION

METHODS

RESULTS

CONCLUSIONS

Overall, these data provide mechanistic understanding of how this novel adjuvant activates immune responses.

简介

佐剂添加到亚单位疫苗中可增强抗原特异性免疫反应。佐剂作用的一种机制是激活固有免疫细胞上的模式识别受体 (PRR)。定植因子 A (BcfA)；一种具有佐剂功能的外膜蛋白，可激活针对和 SARS CoV-2 蛋白抗原的 T1/T17 极化免疫反应。与其他佐剂不同，BcfA 不会引起 T2 反应。

方法

为了了解 BcfA 驱动的 T1/T17 与 T2 激活的机制，我们筛选了 PRR 以鉴定 BcfA 激活的途径。然后，我们使用 TLR4 种系缺失的小鼠测试了该受体在 BcfA 介导的骨髓来源树突状细胞 (BMDC) 激活中的作用，以体外和体内定量共刺激分子表达和细胞因子产生的上调。还在人 PBMC 上测试了活性。

结果

PRR 筛选显示 BcfA 通过鼠 TLR4 激活抗原呈递细胞。BcfA 处理的 WT BMDC 上调了共刺激分子 CD40、CD80 和 CD86 的表达，并产生了 IL-6、IL-12/23 p40 和 TNF-α，而 TLR4 KO BMDC 则未被激活。此外，用 BcfA 刺激的人 PBMC 产生了 IL-6。BcfA 刺激的鼠 BMDC 还表现出对抗原 DQ-OVA 的摄取增加，支持 BcfA 在改善抗原呈递给 T 细胞中的作用。BcfA 进一步激活了鼠肺中的 APC。使用 T 细胞极化系统，我们发现 BcfA 刺激的 BMDC 上清液支持 T 和 T1，同时抑制 T2 基因编程。