Clonally diverse CTL response to a dominant viral epitope recognizes potential epitope variants
Clonally diverse CTL response to a dominant viral epitope recognizes potential epitope variants
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DOI：
10.4049/jimmunol.167.9.4996
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发表时间：
2001-11-01
影响因子：
4.4
通讯作者：
Letvin, NL
中科院分区：
文献类型：
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作者：
Charini, WA;Kuroda, MJ;Letvin, NL
RNA病毒由于易于出错的RNA复制机制而经历快速的序列变异。当在编码B或T细胞表位的RNA区域中出现可行突变时，可以选择能够逃避免疫检测的突变病毒。在对SIVmac感染的Mamu-A*01（+）恒河猴中Gag p11 C（C-M）表位的CTL应答的仔细研究中，已经表明，即使面对累积突变，也可以发生对该表位的CTL识别。为了探索这种识别广度的潜在机制，我们构建了Mamu-A*01四聚体，其区分对表位变体特异性的T细胞。使用这些试剂，我们已经定义了离散的亚群p11 C（C-M）特异性T细胞的交叉反应与细胞呈递变异肽。我们发现，尽管对p11 C（C-M）表位的识别能力一直很强，但单个Mamu-A*01（+）猴识别表位变体的能力在功能上不同。这种功能差异是由变异特异性T细胞的相对数量和感染猴的功能相关TCR库的差异引起的。我们还发现，用仅编码野生型表位序列的DNA疫苗构建体免疫的猴子产生与变体肽交叉反应的p11 C（C-M）特异性CTL。因此，交叉反应性CTL不仅在病毒CTL逃逸突变体的出现和免疫呈递后出现，而且在用显性表位肽序列引发后从头出现。两者合计，我们的研究结果支持的概念，CTL反应的优势病毒表位，虽然高度集中，可以克隆多样性和识别潜在的表位变体。
RNA viruses undergo rapid sequence variation as the result of error-prone RNA replication mechanisms. When viable mutations arise in RNA regions encoding B or T cell epitopes, mutant viruses that can evade immune detection may be selected. In the carefully studied CTL response to the Gag p11C(C-M) epitope in SIVmac-infected Mamu-A*01(+) rhesus monkeys, it has been shown that CTL recognition of that epitope can occur even in the face of accruing mutations. To explore the underlying mechanism for this breadth of recognition, we have constructed Mamu-A*01 tetramers which discriminate T cells specific for epitope variants. Using these reagents we have defined discrete subsets of p11C(C-M)-specific T cells that cross-react with cells presenting variant peptides. We have found that individual Mamu-A*01(+) monkeys differ functionally in their ability to recognize epitope variants despite consistently strong recognition of the p11C(C-M) epitope. This functional difference is accounted for by the relative number of variant-specific T cells and by differences in the functionally relevant TCR repertoire of the infected monkeys. We have also found that monkeys immunized with DNA vaccine constructs encoding only the wild-type epitope sequence develop p11C(C-M)-specific CTL cross-reactive with variant peptides. Thus, cross-reactive CTL do not merely arise secondary to the emergence and immune presentation of viral CTL escape mutants but rather arise de novo following priming with a dominant epitope peptide sequence. Taken together, our results support the concept that the CTL response to a dominant viral epitope, although highly focused, can be clonally diverse and recognize potential epitope variants.