Key Laboratory of Cell Proliferation and Differentiation of the Ministry of Education, School of Life Sciences, Peking University, Beijing, China.
Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, China.
Cell Mol Immunol. 2021 May;18(5):1222-1234. doi: 10.1038/s41423-021-00669-w. Epub 2021 Mar 25.
Aluminum-containing adjuvants have been used for nearly 100 years to enhance immune responses in billions of doses of vaccines. To date, only a few adjuvants have been approved for use in humans, among which aluminum-containing adjuvants are the only ones widely used. However, the medical need for potent and safe adjuvants is currently continuously increasing, especially those triggering cellular immune responses for cytotoxic T lymphocyte activation, which are urgently needed for the development of efficient virus and cancer vaccines. Manganese is an essential micronutrient required for diverse biological activities, but its functions in immunity remain undefined. We previously reported that Mn is important in the host defense against cytosolic dsDNA by facilitating cGAS-STING activation and that Mn alone directly activates cGAS independent of dsDNA, leading to an unconventional catalytic synthesis of 2'3'-cGAMP. Herein, we found that Mn strongly promoted immune responses by facilitating antigen uptake, presentation, and germinal center formation via both cGAS-STING and NLRP3 activation. Accordingly, a colloidal manganese salt (Mn jelly, MnJ) was formulated to act not only as an immune potentiator but also as a delivery system to stimulate humoral and cellular immune responses, inducing antibody production and CD4/CD8 T-cell proliferation and activation by either intramuscular or intranasal immunization. When administered intranasally, MnJ also worked as a mucosal adjuvant, inducing high levels of secretory IgA. MnJ showed good adjuvant effects for all tested antigens, including T cell-dependent and T cell-independent antigens, such as bacterial capsular polysaccharides, thus indicating that it is a promising adjuvant candidate.
含铝佐剂在过去近 100 年的时间里被广泛用于增强数十亿剂疫苗的免疫反应。迄今为止，仅有少数几种佐剂被批准用于人体，其中含铝佐剂是唯一广泛使用的佐剂。然而，人们对高效且安全佐剂的医学需求持续增加，特别是那些能引发细胞免疫反应以激活细胞毒性 T 淋巴细胞的佐剂，这对于开发高效的病毒和癌症疫苗是迫切需要的。锰是一种必需的微量元素，参与多种生物活性，但它在免疫中的功能尚未确定。我们之前曾报道过，锰通过促进 cGAS-STING 的激活在宿主防御细胞质 dsDNA 中起着重要作用，并且锰本身可以独立于 dsDNA 直接激活 cGAS，导致 2'3'-cGAMP 的非传统催化合成。在此，我们发现锰通过激活 cGAS-STING 和 NLRP3 促进抗原摄取、呈递和生发中心形成，从而强烈促进免疫反应。因此，我们制备了胶体锰盐（Mn 胶，MnJ），使其不仅可以作为免疫增强剂，还可以作为一种递送系统，通过肌肉内或鼻内免疫来刺激体液和细胞免疫反应，诱导抗体产生和 CD4/CD8 T 细胞增殖和激活。当经鼻内给药时，MnJ 还可以作为黏膜佐剂，诱导高水平的分泌型 IgA。MnJ 对所有测试的抗原都表现出良好的佐剂效应，包括 T 细胞依赖性和 T 细胞非依赖性抗原，如细菌荚膜多糖，这表明它是一种有前途的佐剂候选物。
