pDCs efficiently process synthetic long peptides to induce functional virus- and tumour-specific T-cell responses
pDCs efficiently process synthetic long peptides to induce functional virus- and tumour-specific T-cell responses
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DOI：
10.1002/eji.201444588
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发表时间：
2014-10-01
影响因子：
5.4
通讯作者：
Plumas, Joel
中科院分区：
文献类型：
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作者：
Aspord, Caroline;Leloup, Claire;Plumas, Joel
强大的细胞介导的免疫是肿瘤免疫控制和保护免受病毒感染所必需的，其中CD 4（+）和CD 8（+）T细胞起着关键作用。合成长肽（SLP）代表了诱导这种组合应答的有吸引力的方式，因为它们含有I类和II类表位。浆细胞样树突状细胞（pDC）交叉呈递SLP的能力尚未被研究;然而，pDC在形成免疫应答中起关键作用，并且已经成为用于免疫治疗的新型载体。使用覆盖CMVpp 65和MelA（分别代表病毒性疾病（巨细胞病毒，CMV）和肿瘤（黑色素瘤））的整个序列的重叠15-mer肽池，我们表明人pDC可以有效地处理SLP。我们的研究结果表明，pDC有效地交叉呈递病毒和肿瘤来源的SLP，并交叉引发广泛的、有效的和长寿命的CD 4（+）和CD 8（+）T细胞应答，从而引发比短肽负载的pDC更有效的免疫应答。这种能力需要通过蛋白酶体进行细胞内加工，并且通过共暴露于TLR 7/9-L而增强。将SLP与pDC组合代表了引发有效免疫应答的强大免疫策略，这是癌症和病毒感染临床成功所需的。
Robust cell-mediated immunity is required for immune control of tumours and protection from viral infections, with both CD4(+) and CD8(+) T cells playing a pivotal role. Synthetic long peptides (SLPs) represent an attractive way to induce such combined responses, as they contain both class I and class II epitopes. The ability of plasmacytoid dendritic cells (pDCs) to cross-present SLPs has not yet been investigated; yet, pDCs play a critical role in shaping immune responses and have emerged as novel vectors for immunotherapy. Using overlapping 15-mer peptide pools covering the entire sequence of CMVpp65 and MelA, representing a viral disease (cytomegalovirus, CMV) and a tumour (melanoma), respectively, we showed that human pDCs can effectively process SLPs. Our results demonstrated that pDCs potently cross-present virus-and tumour-derived SLPs and cross-prime broad-ranging, effective and long-lived CD4(+) and CD8(+) T-cell responses, triggering more efficient immune responses than short peptide loaded pDCs. This ability required intracellular processing by the proteasome and was enhanced by co-exposure to TLR7/9-L. Combining SLPs with pDCs represents a powerful immunotherapeutic strategy to elicit potent immune responses, which are required for clinical success in cancers and viral infections.