Vaccine-Mediated Inhibition of the Transporter Associated with Antigen Processing Is Insufficient To Induce Major Histocompatibility Complex E-Restricted CD8+ T Cells in Nonhuman Primates
Vaccine-Mediated Inhibition of the Transporter Associated with Antigen Processing Is Insufficient To Induce Major Histocompatibility Complex E-Restricted CD8+ T Cells in Nonhuman Primates
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DOI：
10.1128/jvi.00592-19
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发表时间：
2019-10-01
影响因子：
5.4
通讯作者：
Sacha, Jonah B.
中科院分区：
文献类型：
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作者：
Abdulhaqq, Shaheed A.;Wu, Helen;Sacha, Jonah B.
主要组织相容性复合体E (MHC-E)是高度保守的非经典MHC-1b分子，其紧密结合衍生自经典MHC-1a分子前导序列的肽以呈递给自然杀伤细胞。然而，MHC-E 还结合多种外源性和肿瘤性自肽抗原，以呈递给 CD8(+) T 细胞。尽管 MHC-E 限制性 T 细胞启动的决定因素仍然未知，但这些细胞是在感染了含有抑制与抗原加工 (TAP) 相关的转运蛋白的基因的病原体的人类中诱导的。事实上，接种 TAP 抑制的自体树突状细胞疫苗的小鼠会发育出受鼠类 MHC-E 同源物 Qa-1b 限制的 T 细胞。在这里，我们测试了接种表达 TAP 抑制剂的病毒构建体的恒河猴 (RM) 是否会发育出插入特异性 MHC-E 限制性 CD8(+)T 细胞。我们生成了共表达 SIVmac239 Gag 以及三种 TAP 抑制剂之一的病毒构建体：单纯疱疹病毒 2 ICP47、牛疱疹病毒 1 UL49.5 或恒河猴巨细胞病毒 Rh185。每种TAP抑制剂降低MHC-1α分子的表面表达，但不降低表面MHC-E表达。与表面MHC-1a水平的调节一致，TAP抑制减少了MHC-1a限制性CD8(+)T细胞表位的呈递，而不影响MHC-E结合的肽抗原的呈递。用同时表达 SIVmac239 Gag 和 ICP47、UL49.5 或 Rh185 的载体对猕猴进行疫苗接种，产生典型地受 MHC-la 但不受 MHC-E 限制的 Gag 特异性 CD8(+)T 细胞。这些数据表明，与小鼠的结果相比，单独的 TAP 抑制不足以在灵长类动物中引发 MHC-E 限制性 T 细胞反应，并表明其他未知机制控制着识别 MHC-E 结合抗原的 CD8(+) T 细胞的诱导。目标。然而，人们对这些细胞是如何诱导的知之甚少。了解诱导这些 T 细胞的潜在机制将为一系列肿瘤以及病毒和细菌病原体提供强大的新疫苗策略。最近的研究表明 TAP 抑制与 MHC-E 限制性 T 细胞的诱导之间存在联系。我们研究的意义在于证明单独的 TAP 抑制并不能启动 MHC-E 限制性 T 细胞的生成，并表明其他目前未知的机制可以调节其诱导。
Major histocompatibility complex E (MHC-E) is a highly conserved non-classical MHC-lb molecule that tightly binds peptides derived from leader sequences of classical MHC-la molecules for presentation to natural killer cells. However, MHC-E also binds diverse foreign and neoplastic self-peptide antigens for presentation to CD8(+) T cells. Although the determinants of MHC-E-restricted T cell priming remain unknown, these cells are induced in humans infected with pathogens containing genes that inhibit the transporter associated with antigen processing (TAP). Indeed, mice vaccinated with TAP-inhibited autologous dendritic cells develop T cells restricted by the murine MHC-E homologue, Qa-1b. Here, we tested whether rhesus macaques (RM) vaccinated with viral constructs expressing a TAP inhibitor would develop insert-specific MHC-E-restricted CD8(+)T cells. We generated viral constructs co-expressing SIVmac239 Gag in addition to one of three TAP inhibitors: herpes simplex virus 2 ICP47, bovine herpes virus 1 UL49.5, or rhesus cytomegalovirus Rh185. Each TAP inhibitor reduced surface expression of MHC-la molecules but did not reduce surface MHC-E expression. In agreement with modulation of surface MHC-la levels, TAP inhibition diminished presentation of MHC-la-restricted CD8(+)T cell epitopes without impacting presentation of peptide antigen bound by MHC-E. Vaccination of macaques with vectors dually expressing SIVmac239 Gag with ICP47, UL49.5, or Rh185 generated Gag-specific CD8(+)T cells classically restricted by MHC-la but not MHC-E. These data demonstrate that, in contrast to results in mice, TAP inhibition alone is insufficient for priming of MHC-E-restricted T cell responses in primates and suggest that additional unknown mechanisms govern the induction of CD8(+) T cells recognizing MHC-E-bound antigen.IMPORTANCE Due to the near monomorphic nature of MHC-E in the human population and inability of many pathogens to inhibit MHC-E-mediated peptide presentation, MHC-E-restricted T cells have become an attractive vaccine target. However, little is known concerning how these cells are induced. Understanding the underlying mechanisms that induce these T cells would provide a powerful new vaccine strategy to an array of neoplasms and viral and bacterial pathogens. Recent studies have indicated a link between TAP inhibition and induction of MHC-E-restricted T cells. The significance of our research is in demonstrating that TAP inhibition alone does not prime MHC-E-restricted T cell generation and suggests that other, currently unknown mechanisms regulate their induction.