Mechanisms of cytokine synergy essential for vaccine protection against viral challenge
Mechanisms of cytokine synergy essential for vaccine protection against viral challenge
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DOI：
10.1093/intimm/13.7.897
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发表时间：
2001-07-01
影响因子：
4.4
通讯作者：
Berzofsky, JA
中科院分区：
文献类型：
--
作者：
Ahlers, JD;Belyakov, IM;Berzofsky, JA
我们的实验室和其他实验室已经清楚地证明了细胞因子能够将CD 4（+）T-h细胞应答导向T（h）1或T（h）2表型，并增强CD 8（+）细胞毒性T淋巴细胞（CTL）和抗体应答的幅度，但细胞因子对保护性免疫应答的影响尚不清楚。在这里，我们显示了CD 4（+）TO辅助细胞诱导和IFN-γ产生在保护免受表达HIV-1 MN病毒包膜糖蛋白gp 160的重组牛痘病毒的病毒攻击中的重要作用。只有当外源性细胞因子粒细胞巨噬细胞集落刺激因子（GM-CSF）、IL-12和肿瘤坏死因子（TNF）-α的三重组合与肽疫苗共同施用时，才能实现对病毒攻击的完全保护。体内清除CD 4（+）细胞或免疫IFN-γ缺陷小鼠可消除保护作用。GM-CSF、IL-12和TNF-α也协同增强CTL的诱导;然而，在该病毒攻击模型中，CD 8（+）CTL系的过继转移仅提供部分保护。作为体内保护的一种可能机制，我们表明GM-CSF增加了引流淋巴结中抗原呈递树突状细胞的百分比和活性，其中免疫应答开始。我们进一步证明了IL-12和促炎细胞因子TNF-α在驱动IFN-γ产生中的协同作用。因此，IL-12和TNF-α的组合对于T（h）1应答的最佳发展是必不可少的，并且有助于BALB/c小鼠中的CTL诱导，并且由第三种细胞因子GM-CSF补充，其增强抗原呈递。
The ability of cytokines to steer CD4(+) T-h cell responses toward a T(h)1 or T(h)2 phenotype and enhance the magnitude of both CD8(+) cytotoxic T lymphocytes (CTL) and antibody responses has clearly been demonstrated by our lab and others, but the influence of cytokines on protective immune responses is much less clear. Here we show an essential role for CD4(+) TO helper cell induction and IFN-gamma production in protection from viral challenge with a recombinant vaccinia virus expressing HIV-1MN viral envelope glycoprotein gp160. Complete protection from viral challenge is achieved only when the triple combination of exogenous cytokines granulocyte macrophage colony stimulating factor (GM-CSF), IL-12 and tumor necrosis factor (TNF)-alpha are co-administered with the peptide vaccine. In vivo depletion of CD4(+) cells or immunization of IFN-gamma -deficient mice abrogates protection. GM-CSF, IL-12 and TNF-alpha also synergize for the enhanced induction of CTL; however, adoptive transfer of a CD8(+) CTL line afforded only partial protection in this viral challenge model. As a possible mechanism of in vivo protection we show that GM-CSF increases the percentage and activity of antigen-presenting dendritic cells in draining lymph nodes where the immune response is initiated. We further demonstrate synergy between IL-12 and the proinflammatory cytokine TNF-alpha in driving IFN-gamma production. Thus, a combination of IL-12 and TNF-alpha is essential for the optimal development of T(h)1 responses and help for CTL induction in BALB/c mice, and is complemented by a third cytokine, GM-CSF, which enhances antigen presentation.