Squalene emulsion-based vaccine adjuvants stimulate CD8 T cell, but not antibody responses, through a RIPK3-dependent pathway
Squalene emulsion-based vaccine adjuvants stimulate CD8 T cell, but not antibody responses, through a RIPK3-dependent pathway
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DOI：
10.7554/elife.52687
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发表时间：
2020-06-09
期刊：
影响因子：
7.7
通讯作者：
Pulendran, Bali
中科院分区：
文献类型：
--
作者：
Kim, Eui Ho;Woodruff, Matthew C.;Pulendran, Bali
基于角鲨烯的水包油乳剂（SE）疫苗佐剂MF 59已在30多个国家的1亿多人中接种季节性和大流行性流感疫苗。尽管其广泛使用和有效性，其作用机制仍不清楚。在这项研究中，我们证明了用MF 59或其模拟物AddaVax（AV）加可溶性抗原免疫小鼠导致淋巴结和非淋巴组织中的稳健的抗原特异性抗体和CD 8 T细胞应答。免疫触发淋巴结中的快速RIPK 3激酶依赖性坏死性凋亡，其在6小时达到峰值，随后是细胞凋亡的连续波。用明矾加抗原免疫不诱导RIPK 3依赖性信号传导。MF 59或AV诱导的RIPK 3依赖性信号传导对于Batf 3依赖性CD 8（+）DCs向CD 8 T细胞交叉呈递抗原至关重要。与此一致，RIPK 3缺陷型或Batf 3缺陷型小鼠的免疫增强型CD 8 T细胞应答能力受损。然而，CD 8 T细胞反应在MLKL缺陷的小鼠中不受影响，MLKL是坏死性凋亡的下游介质。令人惊讶的是，抗体应答在RIPK 3激酶或Batf 3缺陷小鼠中不受影响。与此相反，抗体反应受损的泛半胱天冬酶抑制剂Z-VAD-FMK的体内给药，但正常的半胱天冬酶-1缺陷小鼠，这表明从凋亡半胱天冬酶的贡献，在诱导抗体反应。这些结果表明，基于角鲨烯乳液的疫苗佐剂分别通过RIPK 3依赖性和非依赖性途径诱导抗原特异性CD 8 T细胞和抗体应答。
The squalene-based oil-in-water emulsion (SE) vaccine adjuvant MF59 has been administered to more than 100 million people in more than 30 countries, in both seasonal and pandemic influenza vaccines. Despite its wide use and efficacy, its mechanisms of action remain unclear. In this study we demonstrate that immunization of mice with MF59 or its mimetic AddaVax (AV) plus soluble antigen results in robust antigen-specific antibody and CD8 T cell responses in lymph nodes and non-lymphoid tissues. Immunization triggered rapid RIPK3-kinase dependent necroptosis in the lymph node which peaked at 6 hr, followed by a sequential wave of apoptosis. Immunization with alum plus antigen did not induce RIPK3-dependent signaling. RIPK3-dependent signaling induced by MF59 or AV was essential for cross-presentation of antigen to CD8 T cells by Batf3-dependent CD8(+) DCs. Consistent with this, RIPK3 deficient or Batf3 deficient mice were impaired in their ability to mount adjuvant-enhanced CD8 T cell responses. However, CD8 T cell responses were unaffected in mice deficient in MLKL, a downstream mediator of necroptosis. Surprisingly, antibody responses were unaffected in RIPK3-kinase or Batf3 deficient mice. In contrast, antibody responses were impaired by in vivo administration of the pan-caspase inhibitor Z-VAD-FMK, but normal in caspase-1 deficient mice, suggesting a contribution from apoptotic caspases, in the induction of antibody responses. These results demonstrate that squalene emulsion-based vaccine adjuvants induce antigen-specific CD8 T cell and antibody responses, through RIPK3-dependent and-independent pathways, respectively.