Peptide requirement for CTL activation reflects the sensitivity to CD3 engagement:: Correlation with CD8αβ versus CD8αα expression
Peptide requirement for CTL activation reflects the sensitivity to CD3 engagement:: Correlation with CD8αβ versus CD8αα expression
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DOI：
10.4049/jimmunol.167.5.2577
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发表时间：
2001-09-01
影响因子：
4.4
通讯作者：
Alexander-Miller, MA
中科院分区：
文献类型：
--
作者：
Cawthon, AG;Lu, HP;Alexander-Miller, MA
在我们之前的研究中，发现对低浓度肽Ag敏感的CTL在过继转移到SCID小鼠中时，在减少病毒负荷方面远远优于那些需要高浓度Ag的CTL。因此，重要的是我们了解控制肽 Ag 需求的机制，以实现在体内选择性扩增这些极其敏感的细胞的长期目标。尽管 TCR 亲和力是影响 CTL 对 Ag 敏感性的参数之一，但我们研究了是否还涉及其他机制。在使用 TCR 转基因小鼠模型的研究中，我们成功生成了具有相同 TCR 亲和力但激活要求截然不同的 CTL。使用肽Ag和抗CD3抗体来激活高亲合力和低亲和力的CTL系，我们发现激活阈值的变化是由于所需的TCR数量的差异造成的。此外，我们观察到，在对 TCR 结合更敏感的 CTL 系中，CD8 αβ 与 CD8 α α 的比率显着更高，这可能导致 CD3 结合后这些 CTL 的激活阈值较低。这些研究确定了一种新机制，通过证明 TCR 参与的敏感性、CD8 αβ 与 αα 的表达水平以及达到激活阈值所需的肽 Ag 量之间的直接相关性，确定 Ag 特异性 CTL 的激活要求。
In our previous studies, CTL that were sensitive to low concentrations of peptide Ag were found to be far superior to those requiring high concentrations of Ag for reducing viral burden when adoptively transferred into SCID mice. Thus it is important that we understand the mechanisms that control the requirement for peptide Ag with the long-term goal of selectively expanding these exquisitely sensitive cells in vivo. Although TCR affinity is one parameter that can affect the CTL sensitivity for Ag, we investigated whether additional mechanisms may also be involved. In studies using a TCR transgenic mouse model, we successfully generated CTL with identical TCR affinity that possess distinctly different activation requirements. Using both peptide Ag and anti-CD3 Ab to activate the CTL lines of high vs low avidity, we found that the variations in activation threshold are the result of differences in the required number of engaged TCR. Additionally, we have observed that the ratio of CD8 alpha beta to CD8 alpha alpha is significantly greater in CTL lines that are more sensitive to TCR engagement, which may contribute to the lower activation threshold of these CTL following CD3 engagement. These studies identify a novel mechanism by which the activation requirements of Ag-specific CTL are determined by demonstrating a direct correlation between the sensitivity to TCR engagement, the expression of levels CD8 alpha beta vs alpha alpha, and the amount of peptide Ag required to reach the threshold for activation.