病毒诱饵配体对 MHC-E 转运的调节是 RhCMV/SIV 疫苗效力所必需的。
Modulation of MHC-E transport by viral decoy ligands is required for RhCMV/SIV vaccine efficacy.
机构信息
Vaccine and Gene Therapy Institute and Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR 97006, USA.
AIDS and Cancer Virus Program, Frederick National Laboratory, Frederick, MD 21702, USA.
出版信息
Science. 2021 Apr 30;372(6541). doi: 10.1126/science.abe9233. Epub 2021 Mar 25.
Abstract
Strain 68-1 rhesus cytomegalovirus (RhCMV) vectors expressing simian immunodeficiency virus (SIV) antigens elicit CD8 T cells recognizing epitopes presented by major histocompatibility complex II (MHC-II) and MHC-E but not MHC-Ia. These immune responses mediate replication arrest of SIV in 50 to 60% of monkeys. We show that the peptide VMAPRTLLL (VL9) embedded within the RhCMV protein Rh67 promotes intracellular MHC-E transport and recognition of RhCMV-infected fibroblasts by MHC-E-restricted CD8 T cells. Deletion or mutation of viral VL9 abrogated MHC-E-restricted CD8 T cell priming, resulting in CD8 T cell responses exclusively targeting MHC-II-restricted epitopes. These responses were comparable in magnitude and differentiation to responses elicited by 68-1 vectors but did not protect against SIV. Thus, Rh67-enabled direct priming of MHC-E-restricted T cells is crucial for RhCMV/SIV vaccine efficacy.
摘要
表达猿猴免疫缺陷病毒 (SIV) 抗原的 68-1 恒河猴巨细胞病毒 (RhCMV) 载体能够引发识别主要组织相容性复合体 II (MHC-II) 和 MHC-E 呈递表位的 CD8 T 细胞，但不能识别 MHC-Ia 呈递表位。这些免疫反应介导了 50%至 60%的猴子中 SIV 的复制停滞。我们发现，嵌入 RhCMV 蛋白 Rh67 中的肽 VMAPRTLLL (VL9) 促进了 RhCMV 感染的成纤维细胞内 MHC-E 的运输和 MHC-E 限制性 CD8 T 细胞的识别。病毒 VL9 的缺失或突变消除了 MHC-E 限制性 CD8 T 细胞的启动，导致仅针对 MHC-II 限制性表位的 CD8 T 细胞反应。这些反应的强度和分化与由 68-1 载体引发的反应相当，但不能预防 SIV。因此，Rh67 实现的 MHC-E 限制性 T 细胞的直接启动对于 RhCMV/SIV 疫苗的功效至关重要。
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