Single-epitope DNA vaccination prevents exhaustion and facilitates a broad antiviral CD8+ T cell response during chronic viral infection
Single-epitope DNA vaccination prevents exhaustion and facilitates a broad antiviral CD8+ T cell response during chronic viral infection
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DOI：
10.4049/jimmunol.173.10.6284
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发表时间：
2004-11-15
影响因子：
4.4
通讯作者：
Thomsen, AR
中科院分区：
文献类型：
--
作者：
Bartholdy, C;Stryhn, A;Thomsen, AR
单特异性抗病毒CD 8（+）T细胞应答的诱导可能会对宿主造成风险，因为诱导的T细胞应答范围较窄。在个体水平上，这可能导致选择CD 8（+）T细胞逃逸变体，特别是在慢性病毒感染期间。其次，针对单一优势表位的先前免疫可能抑制对其他病毒表位的应答，并且这可能导致对宿主群体中循环的逃逸变体的再感染的易感性增加。为了解决这些问题，我们使用编码淋巴细胞性脉络丛脑膜炎病毒（LCMV）免疫显性表位的DNA疫苗诱导了仅由单特异性CD 8（+）T细胞组成的记忆反应。我们分析了H-2（B）和H-2（d）小鼠的CD 8（+）T细胞反应谱和对感染的易感性。引发单特异性CD 8（+）T细胞应答不会使小鼠对病毒变体敏感。因此，接种疫苗的小鼠可以免受LCMV的慢性感染，并且没有证据表明存在生物学相关的病毒逃逸。同时，感染后产生广泛和持续的CD 8（+）T细胞应答，并在H-2（d）小鼠中观察到表位扩散。即使在急性LCMV感染后，DNA疫苗接种也不会显著损害自然诱导的免疫力。因此，在经历正常免疫感染的DNA免疫小鼠中，对其他免疫原性表位的应答未被显著抑制，并且大多数小鼠被保护免受逃逸变体的再攻击。这些发现强调，在适当的情况下，单特异性疫苗可能会诱导有效的保护性免疫。
Induction of a monospecific antiviral CD8(+) T cell response may pose a risk to the host due to the narrow T cell response induced. At the individual level, this may result in selection of CD8(+) T cell escape variants, particularly during chronic viral infection. Second, prior immunization toward a single dominant epitope may suppress the response to other viral epitopes, and this may lead to increased susceptibility to reinfection with escape variants circulating in the host population. To address these issues, we induced a memory response consisting solely of monospecific, CD8(+) T cells by use of DNA vaccines encoding immunodominant epitopes of lymphocytic choriomeningitis virus (LCMV). We analyzed the spectrum of the CD8(+) T cell response and the susceptibility to infection in H-2(b) and H-2(d) mice. Priming for a monospecific, CD8(+) T cell response did not render mice susceptible to viral variants. Thus, vaccinated mice were protected against chronic infection with LCMV, and no evidence indicating biologically relevant viral escape was obtained. In parallel, a broad and sustained CD8(+) T cell response was generated upon infection, and in H-2(d) mice epitope spreading was observed. Even after acute LCMV infection, DNA vaccination did not significantly impair naturally induced immunity. Thus, the response to the other immunogenic epitopes was not dramatically suppressed in DNA-immunized mice undergoing normal immunizing infection, and the majority of mice were protected against rechallenge with escape variants. These findings underscore that a monospecific vaccine may induce efficient protective immunity given the right set of circumstances.