Vaccine adjuvants alter TCR-based selection thresholds
Vaccine adjuvants alter TCR-based selection thresholds
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DOI：
10.1016/j.immuni.2008.03.014
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发表时间：
2008-05-01
期刊：
影响因子：
32.4
通讯作者：
McHeyzer-Williams, Michael G.
中科院分区：
文献类型：
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作者：
Malherbe, Laurent;Mark, Linda;McHeyzer-Williams, Michael G.
蛋白质疫苗接种后T细胞受体（TCR）特异性在体内如何演变对辅助性T（Th）细胞功能的发展至关重要。大多数关于Th细胞区室中克隆选择的模型倾向于基于TCR亲和力的阈值。在此，我们证明了形成储存库的疫苗佐剂不需要Toll样受体（TLR）激动剂来诱导抗原特异性Th细胞应答中的克隆优势。然而，使用TLR - 9和TLR - 4激动剂的易分散佐剂通过提高TCR选择阈值和增强抗原特异性克隆扩增，改变了TCR库的使用。通过这种方式，疫苗佐剂控制了表达与MHC II类分子结合亲和力最高的肽的TCR的Th细胞在局部的聚集。克隆组成的改变是通过一些机制实现的，这些机制阻断了克隆型的局部增殖，且与抗原剂量无关，并非是克隆间竞争的结果。佐剂改变抗原特异性Th细胞克隆组成的这种能力对未来蛋白质亚单位疫苗的设计具有根本的意义。
How T cell receptor (TCR) specificity evolves in vivo after protein vaccination is central to the development of helper T (Th) cell function. Most models of clonal selection in the Th cell compartment favor TCR affinity-based thresholds. Here, we demonstrated that depot-forming vaccine adjuvants did not require Toll-like receptor (TLR) agonists; to induce clonal dominance in antigen-specific Th cell responses. However, readily dispersible adjuvants using TLR-9 and TLR-4 agonists skewed TCR repertoire usage by increasing TCR selection thresholds and enhancing antigen-specific clonal expansion. In this manner, vaccine adjuvants control the local accumulation of Th cells expressing TCR with the highest peptide MHC class II binding. Clonal composition was altered by mechanisms that blocked the local propagation of clonotypes independently of antigen dose and not as a consequence of interclonal competition. This capacity of adjuvants to modify antigen-specific Th cell clonal composition has fundamental implications for the design of future protein subunit vaccines.