Targeting 4-1BB (CD137) to enhance CD8 T cell responses with poxviruses and viral antigens.
Targeting 4-1BB (CD137) to enhance CD8 T cell responses with poxviruses and viral antigens.
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DOI：
10.3389/fimmu.2012.00332
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发表时间：
2012
影响因子：
7.3
通讯作者：
Croft M
中科院分区：
文献类型：
--
作者：
Zhao Y;Tahiliani V;Salek-Ardakani S;Croft M
减毒痘苗病毒(VACV)载体被认为是用于传染病免疫治疗的主要候选疫苗。尽管如此，最近的数据显示，这种衰减水平可能会阻碍保护性CD8 T细胞的高效生成。这表明，可能需要将额外的佐剂样活性与减毒活疫苗结合起来，以实现最佳疫苗接种。针对TNFR家族分子4-1BB(CD137)的刺激性试剂可能代表了这样一种疫苗佐剂。以往的小鼠研究发现，4-1BB可以参与多种病毒感染反应中效应性和记忆性CD8 T细胞的最佳启动，并且4-1BB与激动剂相一致地直接刺激有效地增强CD8 T细胞对这些病毒的应答。相反，我们最近报道了4-1BB在VACV强毒株的应答中没有作用，质疑4-1BB激动剂是否可以作为VACV载体疫苗的有效佐剂。在这里，我们显示激动剂抗4-1BB在感染VACV活毒株和减毒VACV时以及在IFA中给出的VACV多肽免疫期间强烈增强主要病毒特异性效应器CD8 T细胞的反应。然而，只有在感染强毒VACV或多肽疫苗后，CD8T细胞的记忆性积累才会增加，而减毒VACV则不能，这部分与减毒病毒在CD8T细胞上瞬时表达4-1BB的增加有关。因此，我们的数据表明，4-1BB可能是VACV疫苗策略短期增强CD8 T细胞应答的一个有前景的靶向佐剂，但可能需要更多的受体与4-1BB结合，以允许减毒VACV载体对CD8 T细胞的长期免疫。
Attenuated vaccinia virus (VACV) vectors are considered prime vaccine candidates for use in immunotherapy of infectious disease. In spite of this, recent data show that the level of attenuation may hamper the efficient generation of protective CD8 T cells. This suggests that additional adjuvant-like activities may need to be combined with attenuated VACV for optimal vaccination. Stimulatory reagents to the TNFR family molecule 4-1BB (CD137) may represent such an adjuvant for vaccination. Previous murine studies have found that 4-1BB can participate in optimal priming of effector and memory CD8 T cells in response to several virus infections, and concordantly direct stimulation of 4-1BB with agonist reagents effectively boosts the CD8 T cell response against those viruses. In contrast, we recently reported that 4-1BB plays no role in the response to a virulent strain of VACV, questioning whether agonists of 4-1BB will be useful adjuvants for vaccination with VACV vectors. Here we show that agonist anti-4-1BB strongly enhanced the primary viral-specific effector CD8 T cell response during infection with live virulent VACV and attenuated VACV, and during immunization with VACV peptides given in IFA. However, accumulation of memory CD8 T cells was enhanced only following infection with virulent VACV or with peptide vaccination, but not with attenuated VACV, correlating in part with more transient expression of 4-1BB on CD8 T cells with attenuated virus. Our data therefore suggest that 4-1BB may be a promising candidate for targeting as an adjuvant for short-term enhancement of CD8 T cell responses with VACV vaccine strategies, but additional receptors may need to be engaged with 4-1BB to allow long-term CD8 T cell immunity with attenuated VACV vectors.
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影响因子：
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