In vivo triggering through 4-1BB enables Th-independent priming of CTL in the presence of an intact CD28 costimulatory pathway
In vivo triggering through 4-1BB enables Th-independent priming of CTL in the presence of an intact CD28 costimulatory pathway
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DOI：
10.4049/jimmunol.168.8.3755
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发表时间：
2002-04-15
影响因子：
4.4
通讯作者：
Offringa, R
中科院分区：
文献类型：
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作者：
Diehl, L;van Mierlo, GJD;Offringa, R
通过体内施用激动性抗 4-1BB Ab 来触发 TNFR 家族成员 4-1BB，从而向 CTL 传递强大的共刺激信号。我们发现该信号可以有效替代 CD4(+) T 细胞帮助交叉启动肿瘤特异性 CTL 免疫的需要。此外，4-1BB Ab 可以将原本具有耐受性的肽疫苗转化为能够有效启动 CTL 的制剂。初始 CTL 的初始激活可以在没有 4-1BB 共刺激的情况下发生，但该信号可以增加 Ag 刺激的 CTL 的存活率。由于初始 CTL 在其表面不表达 4-1BB，因此对 4-1BB 触发的敏感性取决于该受体先前的上调。我们证明这需要 TCR 刺激和 CD28 依赖性共刺激。因此，阻断 CD28 共刺激途径会消除激动性抗 4-1BB Ab 触发 Th 独立 CTL 免疫的能力。总之，我们的数据表明，4-1BB 介导的生存信号位于 Ag 特异性 TCR 触发和初始 CTL 的 CD28 依赖性共刺激的下游。 4-IBB 触发对 CTL 反应的诱导、放大和持续的强大影响为提高癌症疫苗的效力提供了一种新策略。
Triggering of 4-1BB, a member of the TNFR family, through in vivo administration of agonistic anti-4-1BB Ab delivers a powerful costimulatory signal to CTL. We found this signal to effectively replace the need for CD4(+) T cell help in the cross-priming of tumor-specific CTL immunity. Furthermore, 4-1BB Ab can convert an otherwise tolerogenic peptide vaccine into a formulation capable of efficient CTL priming. Initial activation of naive CTL can occur in the absence of 4-1BB costimulation, but this signal permits increased survival of Ag-stimulated CTL. Because naive CTL do not express 4-1BB at their surface, susceptibility to 4-1BB triggering depends on prior up-regulation of this receptor. We show that this requires both stimulation of the TCR and CD28-dependent costimulation. Accordingly, blockade of the CD28-costimulatory pathway abrogates the capacity of agonistic anti-4-1BB Ab to trigger Th-independent CTL immunity. In conclusion, our data reveal that the 4-1BB-mediated survival signal is positioned downstream of Ag-specific TCR triggering and CD28-dependent costimulation of naive CTL. The powerful effects of 4-IBB triggering on the induction, amplification, and persistence of CTL responses provide a novel strategy for increasing the potency of vaccines against cancers.