Cytotoxic T lymphocytes to an unmutated tumor rejection antigen P1A: normal development but restrained effector function in vivo.
Cytotoxic T lymphocytes to an unmutated tumor rejection antigen P1A: normal development but restrained effector function in vivo.
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DOI：
10.1084/jem.189.5.811
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发表时间：
1999-03-01
影响因子：
15.3
通讯作者：
Liu, Y
中科院分区：
文献类型：
--
作者：
Sarma, S;Guo, Y;Guilloux, Y;Lee, C;Bai, X F;Liu, Y
未突变的肿瘤抗原被选为肿瘤疫苗的主要候选者，因为它们在多种肿瘤谱系上表达。一个关键的问题是未突变的肿瘤抗原是否在正常细胞中表达，如果是这样，这种表达是否对细胞毒性T淋巴细胞（CTL）反应施加了特殊的限制。在这项研究中，我们使用转基因的方法来研究的发展和效应功能的T细胞特异性P1 A，原型未突变的肿瘤抗原。我们在这里报告，虽然P1 A在正常组织，包括淋巴组织中表达水平较低，P1 A特异性转基因T细胞发育正常，并保持对P1 A抗原的高度反应。胸腺中P1 A抗原的转基因表达诱导T细胞克隆缺失的事实表明，正常造血细胞可以加工和呈递P1 A抗原，并且P1 A特异性T细胞对克隆缺失敏感。由此推断，由于胸腺中P1 A的低表达，P1 A特异性T细胞一定已经逃脱了克隆缺失。有趣的是，尽管T细胞抗原受体（TCR）转基因小鼠中绝大多数T细胞对P1 A具有特异性，但这些小鼠对表达P1 A的浆细胞瘤的抵抗力并不比非转基因同窝出生的小鼠高。此外，当相同的TCR转基因小鼠同时用B7-1+和B7-1-肿瘤攻击时，只有B7-1+肿瘤被排斥。因此，尽管P1 A可以是肿瘤排斥抗原，但P1 A特异性CTL的效应子功能在体内受到抑制。这些结果对肿瘤免疫治疗策略具有重要意义。
Unmutated tumor antigens are chosen as primary candidates for tumor vaccine because of their expression on multiple lineages of tumors. A critical issue is whether unmutated tumor antigens are expressed in normal cells, and if so, whether such expression imposes special restrictions on cytotoxic T lymphocyte (CTL) responses. In this study, we use a transgenic approach to study the development and effector function of T cells specific for P1A, a prototypical unmutated tumor antigen. We report here that although P1A is expressed at low levels in normal tissues, including lymphoid tissues, the P1A-specific transgenic T cells develop normally and remain highly responsive to the P1A antigen. The fact that transgenic expression of P1A antigen in the thymus induces T cell clonal deletion demonstrates that normal hematopoietic cells can process and present the P1A antigen and that P1A-specific T cells are susceptible to clonal deletion. By inference, P1A-specific T cells must have escaped clonal deletion due to low expression of P1A in the thymus. Interestingly, despite the fact that an overwhelming majority of T cells in the T cell receptor for antigen (TCR)–transgenic mice are specific for P1A, these mice are no more resistant to a P1A-expressing plasmocytoma than nontransgenic littermates. Moreover, when the same TCR-transgenic mice were challenged simultaneously with B7-1+ and B7-1− tumors, only B7-1+ tumors were rejected. Therefore, even though P1A can be a tumor rejection antigen, the effector function of P1A-specific CTL is restrained in vivo. These results have important implications for the strategy of tumor immunotherapy.