Addition of a prominent epitope affects influenza a virus-specific CD8+ T cell immunodominance hierarchies when antigen is limiting
Addition of a prominent epitope affects influenza a virus-specific CD8+ T cell immunodominance hierarchies when antigen is limiting
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DOI：
10.4049/jimmunol.177.5.2917
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发表时间：
2006-09-01
影响因子：
4.4
通讯作者：
Turner, Stephen J.
中科院分区：
文献类型：
--
作者：
Jenkins, Misty Rayna;Webby, Richard;Turner, Stephen J.
使用反向遗传学策略将OVA肽（氨基酸序列SIINFEKL; OVA（257-264））插入A/PR 8（H1N1）和A/HKx 31（H3 N2）甲型流感病毒的神经氨酸酶茎中。初步表征确定K（B）OVA（257）呈递在PR 8-OVA和HK-OVA感染的靶标上，而不显著改变D-B核蛋白（NP）（366）呈递。在初次和二次鼻内攻击后，K（B）OVA（257）-和（DNP 366）-N-B-特异性CTL扩增水平相似。有趣的是，虽然可变，但免疫显性K（B）OVA（257）特异性应答的存在导致D-B酸性聚合酶（224）-和K-B碱性聚合酶亚基1（703）-特异性应答减少，但不导致（DNP 366）-N-B-特异性应答减少，并且不改变内源性甲型流感病毒特异性免疫显性等级。然而，通过腹膜内途径用HK-OVA攻击PR 8-OVA致敏的小鼠，从而限制Ag剂量，导致测量的所有甲型流感病毒特异性应答的幅度降低。在接受大量K（B）OVA（257）特异性TCR转基因T细胞的小鼠的初次呼吸道HK-OVA感染后，也观察到对天然表位的CTL应答的类似降低。因此，在感染过程中，个体病毒特异性CTL应答的产生是独立调节的。然而，在其中Ag是限制性的或高前体频率的情况下，免疫显性CTL应答的存在可以影响其他特定群体的大小。因此，根据T细胞前体库的大小和Ag呈递的模式，添加主要表位可以减少内源性流感特异性CD 8（+）T细胞应答的大小，尽管从未达到完全受损的程度。
A reverse genetics strategy was used to insert the OVA peptide (amino acid sequence SIINFEKL; OVA(257-264)) into the neuraminidase stalk of both the A/PR8(H1N1) and A/HKx31 (H3N2) influenza A viruses. Initial characterization determined that K(b)OVA(257) is presented on targets infected with PR8-OVA and HK-OVA without significantly altering D-b nucleoprotein (NP)(366) presentation. There were similar levels of K(b)OVA(257)- and (DNP366)-N-b-specific CTL expansion following both primary and secondary intranasal challenge. Interestingly, while variable, the presence of the immunodominant K(b)OVA(257)-specific response resulted in diminished D-b acidic polymerase(224)- and K-b basic polymerase subunit 1(703)-, but not (DNP366)-N-b-specific responses and didn't alter endogenous influenza A virus-specific immunodominance hierarchies. However, challenging PR8-OVA-primed mice with HK-OVA via the i.p. route, and thereby limiting Ag dose, led to a reduction in the magnitude of all the influenza A virus-specific responses measured. A similar reduction in CTL response to native epitopes was also seen following primary respiratory HK-OVA infection of mice that received substantial numbers of K(b)OVA(257)-specific TCR transgenic T cells. Thus, during the course of infection, the generation of individual virus-specific CTL responses is independently regulated. However, in cases in which Ag is limiting, or high precursor frequency, the presence of immunodominant CTL responses can impact on the magnitude of other specific populations. Therefore, depending on both the size of the T cell precursor pool and the mode of Ag presentation, the addition of a major epitope can diminish the size of endogenous, influenza-specific CD8(+) T cell responses, although never to the point that these are totally compromised.