Circumvention of regulatory CD4+ T cell activity during cross-priming strongly enhances T cell-mediated immunity
Circumvention of regulatory CD4+ T cell activity during cross-priming strongly enhances T cell-mediated immunity
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DOI：
10.1002/eji.200737966
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发表时间：
2008-06-01
影响因子：
5.4
通讯作者：
Kastenmueller, Kathrin
中科院分区：
文献类型：
--
作者：
Heit, Antje;Gebhardt, Friedemann;Kastenmueller, Kathrin
用纯化抗原免疫是一种安全实用的疫苗接种策略，但通常不能诱导持续的CD8（+）T细胞介导的抗细胞内病原体的保护作用。改善这些疫苗的CD8（+）T细胞免疫原性的大多数努力集中在佐剂的共施用以支持交叉呈递和树突状细胞成熟。此外，已经表明，在引发阶段期间的CD4（+）T细胞帮助有助于产生保护性CD8（+）记忆T细胞。在这份报告中，我们证明了CD4（+）T细胞的耗竭矛盾地增强了蛋白疫苗接种后持久的CD8介导的保护性免疫。功能性和遗传性体内失活实验将这种增强主要归因于MHC II类限制性CD4（+）调节性T细胞（Treg），其似乎在生理上抑制向长寿命效应记忆T细胞的分化过程。由于在功能方面，Treg的这种抑制作用大大超过了常规CD4（+）T细胞帮助的积极作用，因此即使所有CD4（+）T细胞都不存在或缺乏MHC II类介导的对引发树突状细胞的相互作用，也会导致CD8（+）T细胞免疫原性增强。这些发现对于改进针对细胞内病原体或肿瘤的疫苗具有重要意义，特别是在具有高活性Treg的患者中。
Immunization with purified antigens is a safe and practical vaccination strategy but is generally unable to induce sustained CD8(+) T cell-mediated protection against intracellular pathogens. Most efforts to improve the CD8(+) T cell immunogenicity of these vaccines have focused on co-administration of adjuvant to support cross-presentation and dendritic cell maturation. In addition, it has been shown that CD4(+) T cell help during the priming phase contributes to the generation of protective CD8(+) memory T cells. In this report we demonstrate that the depletion of CD4(+) T cells paradoxically enhances long-lasting CD8-mediated protective immunity upon protein vaccination. Functional and genetic in vivo inactivation experiments attribute this enhancement primarily to MHC class II-restricted CD4(+) regulatory T cells (Treg), which appear to physiologically suppress the differentiation process towards long-living effector memory T cells. Since, in functional terms, this suppression by Treg largely exceeds the positive effects of conventional CD4(+) T cell help, even the absence of all CD4(+) T cells or lack of MHC class II-mediated interactions on priming dendritic cells result in enhanced CD8(+) T cell immunogenicity. These findings have important implications for the improvement of vaccines against intracellular pathogens or tumors, especially in patients with highly active Treg.