TCR Affinity for In Vivo Peptide-Induced Thymic Positive Selection Fine-Tunes TCR Responsiveness of Peripheral CD8+ T Cells
TCR Affinity for In Vivo Peptide-Induced Thymic Positive Selection Fine-Tunes TCR Responsiveness of Peripheral CD8+ T Cells
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DOI：
10.4049/jimmunol.1900097
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发表时间：
2019-08-15
影响因子：
4.4
通讯作者：
Takahama, Yousuke
中科院分区：
文献类型：
--
作者：
Khanom, Umme Shahina;Ohigashi, Izumi;Takahama, Yousuke
胸腺中TCR与自身肽/MHC复合物（pMHC）相互作用的亲和力严重影响新表达TCR的未成熟胸腺细胞。以前的胎儿胸腺器官培养实验表明，胸腺TCR/pMHC相互作用的亲和力的差异不仅决定了胸腺细胞的命运之间的积极和消极的选择，但也影响积极选择的胸腺细胞的Ag反应。在目前的研究中，我们研究了在胸腺中的阳性选择过程中TCR/pMHC亲和力是否会进一步影响外周成熟T细胞的Ag反应性。为此，将OVA肽变体体内给予TAP 1缺陷型OT-I/TCR转基因小鼠，其中T细胞发育在CD 4（+）CD 8（+）胸腺细胞处被阻止，因为胸腺APC中缺乏自身pMHC呈递。我们发现一组肽变体诱导胸腺和外周中OT-I CD 8（+）T细胞的瞬时产生。我们还注意到，在成年小鼠体内检测到的阳性和阴性选择的亲和力阈值高于在体外胎胸腺器官培养实验中测得的亲和力阈值。有趣的是，我们进一步发现，对阳性选择肽的亲和力成比例地影响外周初始CD 8（+）T细胞的TCR反应性。这些结果表明，肽的体内施用可以促进胸腺中的T细胞选择，并且在阳性选择期间对TCR/pMHC相互作用的亲和力微调外周T细胞的Ag应答性。
The affinity for TCR interactions with self-peptide/MHC complexes (pMHC) in the thymus critically affects immature thymocytes that newly express TCRs. Previous fetal thymus organ culture experiments have indicated that difference in the affinity for thymic TCR/pMHC interactions not only determines thymocyte fate between positive and negative selection, but also affects Ag responsiveness of positively selected thymocytes. In the current study, we examined whether TCR/pMHC affinity during positive selection in the thymus would further affect Ag responsiveness of mature T cells in the periphery. To do so, OVA peptide variants were in vivo administered to TAP1-deficient OT-I/TCR-transgenic mice in which T cell development was otherwise arrested at CD4(+)CD8(+) thymocytes because of the lack of self-pMHC presentation in thymic APCs. We found that a group of peptide variants induced the transient generation of OT-I CD8(+) T cells in the thymus and the periphery. We also noticed that the affinity threshold for positive and negative selection detected in adult mice in vivo was higher than that measured in fetal thymus organ culture experiments in vitro. Interestingly, we further found that the affinity for positively selecting peptides proportionally affected TCR responsiveness of peripheral naive CD8(+) T cells. These results indicate that in vivo administration of a peptide can promote T cell selection in the thymus and the affinity for TCR/pMHC interaction during positive selection fine-tunes Ag responsiveness of peripheral T cells.