Division of Inflammation Biology, La Jolla Institute for Allergy &Immunology, La Jolla, California 92037, USA.
Institute of Arboviruses, School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325000, China.
Nat Microbiol. 2017 Mar 13;2:17036. doi: 10.1038/nmicrobiol.2017.36.
CD8 T cells play an important role in controlling Flavivirus infection, including Zika virus (ZIKV). Here, we have identified 25 HLA-B0702-restricted epitopes and 1 HLA-A0101-restricted epitope using interferon (IFN)-γ enzyme-linked immunospot (ELISPOT) and intracellular cytokine staining (ICS) in ZIKV-infected IFN-α/β receptor-deficient HLA transgenic mice. The cross-reactivity of ZIKV epitopes to dengue virus (DENV) was tested using IFN-γ-ELISPOT and IFN-γ-ICS on CD8 T cells from DENV-infected mice, and five cross-reactive HLA-B*0702-binding peptides were identified by both assays. ZIKV/DENV cross-reactive CD8 T cells in DENV-immune mice expanded post ZIKV challenge and dominated in the subsequent CD8 T cell response. ZIKV challenge following immunization of mice with ZIKV-specific and ZIKV/DENV cross-reactive epitopes elicited CD8 T cell responses that reduced infectious ZIKV levels, and CD8 T cell depletions confirmed that CD8 T cells mediated this protection. These results identify ZIKV-specific and ZIKV/DENV cross-reactive epitopes and demonstrate both an altered immunodominance pattern in the DENV-immune setting relative to naive, as well as a protective role for epitope-specific CD8 T cells against ZIKV. These results have important implications for ZIKV vaccine development and provide a mouse model for evaluating anti-ZIKV CD8 T cell responses of human relevance.
CD8 T 细胞在控制黄病毒感染（包括寨卡病毒）中发挥着重要作用。在这里，我们通过 IFN-γ 酶联免疫斑点（ELISPOT）和细胞内细胞因子染色（ICS）在感染寨卡病毒的 IFN-α/β 受体缺陷型 HLA 转基因小鼠中鉴定了 25 个 HLA-B0702 限制性表位和 1 个 HLA-A0101 限制性表位。使用 IFN-γ-ELISPOT 和 IFN-γ-ICS 测试寨卡病毒表位与登革热病毒（DENV）的交叉反应性，在感染 DENV 的小鼠的 CD8 T 细胞中进行，通过两种检测方法鉴定出 5 个交叉反应性 HLA-B*0702 结合肽。在 DENV 免疫的小鼠中，寨卡病毒/登革热病毒交叉反应性 CD8 T 细胞在寨卡病毒挑战后扩增，并在随后的 CD8 T 细胞反应中占主导地位。用寨卡病毒特异性和寨卡病毒/登革热病毒交叉反应性表位免疫小鼠后，再用寨卡病毒进行挑战，引发了 CD8 T 细胞反应，降低了感染性寨卡病毒水平，CD8 T 细胞耗竭证实 CD8 T 细胞介导了这种保护作用。这些结果鉴定了寨卡病毒特异性和寨卡病毒/登革热病毒交叉反应性表位，并证明了在 DENV 免疫背景下，相对于未免疫的情况，免疫优势模式发生了改变，以及表位特异性 CD8 T 细胞对寨卡病毒的保护作用。这些结果对寨卡病毒疫苗的发展具有重要意义，并为评估人类相关抗寨卡病毒 CD8 T 细胞反应提供了一个小鼠模型。
