An essential role of the avidity of T-cell receptor in differentiation of self-antigen-reactive CD8+ T cells
An essential role of the avidity of T-cell receptor in differentiation of self-antigen-reactive CD8+ T cells
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T 细胞受体的亲和力在自身抗原反应性 CD8 T 细胞分化中的重要作用
DOI：
10.1097/cji.0000000000000114
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发表时间：
2016
影响因子：
3.9
通讯作者：
Sugiyama H
中科院分区：
文献类型：
--
作者：
Kondo K;Fujiki F;Nakajima H;Yatsukawa E;Morimoto S;Tatsumi N;Nishida S;Nakata J;Oka Y;Tsuboi A;Hosen N;Oji Y;Sugiyama H
许多研究表明，T细胞受体（TCR）的亲合力在T细胞命运中起着至关重要的作用。然而，大多数这些发现来自于对非自身抗原特异性CD 8 + T细胞的分析，并且关于TCR亲合力在自身抗原特异性CD 8 + T细胞的命运中的作用知之甚少。Wilms肿瘤基因1（WT 1）蛋白是最适合解决这个问题的自身抗原，因为WT 1蛋白是高度免疫原性的典型自身抗原。在这里，我们从鼠WT 1肽（RMFPNAPYL）特异性细胞毒性T淋巴细胞（WT 1-CTL）中分离出2种不同的功能性TCR，TCR 1和TCR 2，并在T和B细胞缺陷和重建条件下产生TCR 1-逆转录（Rg）和TCR 2-Rg小鼠。TCR 1转导的CD 8 + T（TCR 1-T）细胞对WT 1肽的亲合力比TCR 2转导的CD 8 + T（TCR 2-T）细胞高约2倍。细胞因子的生产概况和细胞表面表型表明，在这两种条件下，TCR 1-T细胞比TCR 2-T细胞更分化。因此，TCR亲合力高于TCR 2-T细胞的TCR 1-T细胞与TCR 2-T细胞相比更分化。此外，在T和B细胞重建条件下发育的TCR 1-T细胞显示出对内源性WT 1表达肿瘤细胞的细胞毒性，而在相同条件下发育的TCR 2 T细胞则没有。因此，通过在相同的遗传背景下成功建立仅TCR亲合力不同的两种不同的WT 1-CTL，首次证明了TCR亲合力在自身抗原反应性T细胞的分化中起重要作用。目前的研究结果应该为阐明自身抗原反应性T细胞（包括肿瘤抗原反应性T细胞）的分化机制提供了一种见解。
Many studies demonstrated crucial roles of avidity of T-cell receptor (TCR) in T-cell fate. However, majority of these findings resulted from analysis of non–self-antigen-specific CD8+ T cells, and little is known about roles of TCR avidity in the fate of self-antigen-specific CD8+ T cells. Wilms tumor gene 1 (WT1) protein is a self-antigen most suitable for addressing this issue because WT1 protein is a highly immunogenic, typical self-antigen. Here, we isolated 2 distinct and functional TCRs, TCR1 and TCR2, from murine WT1 peptide (RMFPNAPYL)-specific cytotoxic T lymphocytes (WT1-CTLs) and generated TCR1-retrogenic (Rg) and TCR2-Rg mice under T and B-cell-deficient and-reconstituted conditions. TCR1-transduced CD8+ T (TCR1-T) cells had approximately 2-fold higher avidity to WT1 peptide than TCR2-transduced CD8+ T (TCR2-T) cells. Cytokine production profiles and cell surface phenotypes showed that TCR1-T cells were more differentiated than TCR2-T cells under both conditions. Therefore, TCR1-T cells with TCR avidity higher than that of TCR2-T cells are more differentiated compared with TCR2-T cells. Furthermore, TCR1-T cells that developed under T and B-cell-reconstituted conditions displayed cytotoxicity against endogenously WT1-expressing tumor cells, whereas TCR2 T cells that developed under the same conditions did not. Thus, it was demonstrated, for the first time, that TCR avidity played an essential role in differentiation of self-antigen-reactive T cells, through the success of establishment of two distinct WT1-CTLs with a difference in only TCR avidity under the identical genetic background. Present results should provide us with an insight for elucidation of the differentiation mechanisms of self-antigen-reactive T cells, including tumor antigen–reactive T cells.