Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.
Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.
PLoS Pathog. 2021 Mar 18;17(3):e1009324. doi: 10.1371/journal.ppat.1009324. eCollection 2021 Mar.
The development of safe subunit vaccines requires adjuvants that augment immunogenicity of non-replicating protein-based antigens. Current vaccines against infectious diseases preferentially induce protective antibodies driven by adjuvants such as alum. However, the contribution of antibody to host defense is limited for certain classes of infectious diseases such as fungi, whereas animal studies and clinical observations implicate cellular immunity as an essential component of the resolution of fungal pathogens. Here, we decipher the structural bases of a newly identified glycoprotein ligand of Dectin-2 with potent adjuvancy, Blastomyces endoglucanase-2 (Bl-Eng2). We also pinpoint the developmental steps of antigen-specific CD4+ and CD8+ T responses augmented by Bl-Eng2 including expansion, differentiation and tissue residency. Dectin-2 ligation led to successful systemic and mucosal vaccination against invasive fungal infection and Influenza A infection, respectively. O-linked glycans on Bl-Eng2 applied at the skin and respiratory mucosa greatly augment vaccine subunit- induced protective immunity against lethal influenza and fungal pulmonary challenge.
安全亚单位疫苗的开发需要佐剂来增强非复制性蛋白基础抗原的免疫原性。目前针对传染病的疫苗优先诱导佐剂（如铝佐剂）驱动的保护性抗体。然而，对于某些类别的传染病（如真菌），抗体对宿主防御的贡献是有限的，而动物研究和临床观察表明细胞免疫是清除真菌病原体的一个重要组成部分。在这里，我们揭开了一种新发现的 Dectin-2 糖蛋白配体的结构基础，该配体具有很强的佐剂活性，即芽生菌内葡聚糖酶-2（Bl-Eng2）。我们还确定了 Bl-Eng2 增强的抗原特异性 CD4+和 CD8+T 反应的发育步骤，包括扩增、分化和组织归巢。Dectin-2 配体可成功进行全身和黏膜接种，以预防侵袭性真菌感染和甲型流感感染。Bl-Eng2 的 O-连接糖在皮肤和呼吸道黏膜上的应用大大增强了疫苗亚单位诱导的对致命流感和真菌性肺挑战的保护性免疫。
