Functional differences between low- and high-affinity CD8(+) T cells in the tumor environment.
Functional differences between low- and high-affinity CD8(+) T cells in the tumor environment.
复制标题
DOI：
10.4161/onci.21285
复制
发表时间：
2012-11-01
期刊：
影响因子：
7.2
通讯作者：
Sherman LA
中科院分区：
文献类型：
--
作者：
Bos R;Marquardt KL;Cheung J;Sherman LA
弱的T细胞抗原受体（TCR）-配体相互作用足以激活幼稚的CD 8 + T细胞，但通常不会导致肿瘤根除。TCR亲和力的差异如何影响免疫抑制肿瘤环境中T细胞功能的调节尚未研究。我们已经检查了高与低亲和力CD 8 + T细胞的功能差异，并且我们观察到肿瘤内的浸润、积累、存活和细胞毒性受到TCR-配体相互作用的强度的严重影响。此外，发现高亲和力CD 8 + T细胞表现出较低的抑制性分子表达，包括PD-1、LAG-3和NKG 2A，因此对抑制机制较不敏感。发现干扰素γ和自分泌白细胞介素-2都影响这些分子的表达水平。有趣的是，尽管高亲和力CD 8 + T细胞在其实现肿瘤根除的能力方面上级于低亲和力CD 8 + T细胞，但它们可以通过肿瘤特异性CD 4 + T细胞的存在而进一步改善。这些发现说明了TCR亲和力和肿瘤特异性CD 4在肿瘤免疫治疗中的重要性。
Weak T-cell antigen receptor (TCR)-ligand interactions are sufficient to activate naïve CD8+ T cells, but generally do not result in tumor eradication. How differences in TCR affinity affect the regulation of T-cell function in an immunosuppressive tumor environment has not been investigated. We have examined the functional differences of high- vs. low-affinity CD8+ T cells and we observed that infiltration, accumulation, survival and cytotoxicity within the tumor are severely impacted by the strength of TCR-ligand interactions. In addition, high-affinity CD8+ T cells were found to exhibit lower expression of inhibitory molecules including PD-1, LAG-3 and NKG2A, thus being less susceptible to suppressive mechanisms. Interferon γ and autocrine interleukin-2 were both found to influence the level of expression of these molecules. Interestingly, although high-affinity CD8+ T cells were superior to low-affinity CD8+ T cells in their ability to effect tumor eradication, they could be further improved by the presence of tumor specific CD4+ T cells. These findings illustrate the importance of both TCR affinity and tumor-specific CD4 help in tumor immunotherapy.