Peptide variants of viral CTL epitopes mediate positive selection and emigration of Ag-specific thymocytes in vivo
Peptide variants of viral CTL epitopes mediate positive selection and emigration of Ag-specific thymocytes in vivo
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DOI：
10.4049/jimmunol.173.2.1140
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发表时间：
2004-07-15
影响因子：
4.4
通讯作者：
Reinherz, EL
中科院分区：
文献类型：
--
作者：
Fridkis-Hareli, M;Reche, PA;Reinherz, EL
在发育过程中，携带tcr的胸腺细胞被积极选择输出到成熟的外周T淋巴细胞池中，tcr介导与mhc结合的自肽的低亲和力相互作用。因此，外源性给药某些与同源Ags相比TCR亲和力降低的改变肽配体（APL）可能为诱导所需TCR特异性成熟提供了一种工具。为了验证这种“胸腺疫苗”的概念，我们分别设计了与淋巴细胞性脉络丛脑膜炎病毒特异性P14-和水疱性口炎病毒特异性n15 - tcr相关的病毒CTL表位gp33-41和水疱性口炎病毒核蛋白八肽N52-59的APL，并使用辐照嵌合体检测了它们对体内胸腺细胞的影响。用P14 RAG2(-/-) （Ly-5.2）或N15 RAG2(-/-) （Ly-5.2）转基因小鼠骨髓中的T细胞祖细胞重组辐照过的同源（Ly-5.1）小鼠注射APL，导致表达相关特异性的T细胞阳性选择。此外，这些变异导致病毒特异性T细胞输出到淋巴结，但不诱导T细胞增殖。这些发现表明成熟T细胞库可以通过操纵胸腺选择通过体内肽管理而改变。
During development, thymocytes carrying TCRs mediating low-affinity interactions with MHC-bound self-peptides are positively selected for export into the mature peripheral T lymphocyte pool. Thus, exogenous administration of certain altered peptide ligands (APL) with reduced TCR affinity relative to cognate Ags may provide a tool to elicit maturation of desired TCR specificities. To test this "thymic vaccination" concept, we designed APL of the viral CTL epitopes gp33-41 and vesicular stomatitis virus nucleoprotein octapeptide N52-59 relevant for the lymphocytic choriomeningitis virus-specific P14- and vesicular stomatitis virus-specific N15-TCRs, respectively, and examined their effects on thymocytes in vivo using irradiation chimeras. Injection of APL into irradiated congenic (Ly-5.1) mice, reconstituted with T cell progenitors from the bone marrow of P14 RAG2(-/-) (Ly-5.2) or N15 RAG2(-/-) (Ly-5.2) transgenic mice, resulted in positive selection of T cells expressing the relevant specificity. Moreover, the variants led to export of virus-specific T cells to lymph nodes, but without inducing T cell proliferation. These findings show that the mature T cell repertoire can be altered by in vivo peptide administration through manipulation of thymic selection.