CD8 T cell sensory adaptation dependent on TCR avidity for self-antigens
CD8 T cell sensory adaptation dependent on TCR avidity for self-antigens
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DOI：
10.4049/jimmunol.175.11.7388
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发表时间：
2005-12-01
影响因子：
4.4
通讯作者：
Di Bartolo, V
中科院分区：
文献类型：
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作者：
Marquez, ME;Ellmeier, W;Di Bartolo, V
T 细胞激活阈值的调整可能是控制自身反应性的一种机制。为了研究其在体内的发生，我们通过在选择后的 CD8 胸腺细胞和 T 细胞中表达 Zap70 功能获得突变体 (ZAP-YEEI)，设计了一种具有增加的 TCR 依赖性兴奋性的转基因小鼠模型。在携带 ZAP-YEEI 的 CD8 T 细胞中检测到用于激活 T 细胞的 Zap70 底物连接子的基础磷酸化增加。然而，这些细胞并未被激活，但 TCR 和 CD5 水平降低。此外，它们产生的细胞因子含量较低，并且在激活 T 细胞和 ERK 时表现出更快的接头去磷酸化。通过在不存在 TCR/spMHC 相互作用的情况下培养细胞，可以恢复正常的 TCR 水平和细胞因子产生，这证明了外周 T 细胞反应的动态调节。通过在 P14 或 HY TCR 转基因背景中表达 ZAP-YEEI，研究了自身配体的亲和力对这种感觉适应的影响。出乎意料的是，双转基因动物在双阳性胸腺细胞中过早表达 ZAP-YEEI，但没有观察到选择过程的明显改变。相反，ZAP-YEEI 引起的 TCR 和 CD5 表达的改变表明信号调谐发生在胸腺成熟过程中。重要的是，尽管 P14 X ZAP-YEEI 外周 CD8 T 细胞数量减少，Ag 诱导的细胞因子产生较低，淋巴细胞减少驱动的增殖有限，但 HY X ZAP-YEEI 细胞的外周存活/扩增和 Ag 反应性增强。我们的数据为中枢和外周感觉 T 细胞适应作为 TCR 对自身配体和信号水平的亲和力的函数诱导提供了支持。这可能有助于缓冲过多的自身反应性，同时优化 TCR 库的使用。
Adaptation of the T cell activation threshold may be one mechanism to control autoreactivity. To investigate its occurrence in vivo, we engineered a transgenic mouse model with increased TCR-dependent excitability by expressing a Zap70 gain-of-function mutant (ZAP-YEEI) in postselection CD8 thymocytes and T cells. Increased basal phosphorylation of the Zap70 substrate linker for activation of T cells was detected in ZAP-YEEI-bearing CD8 T cells. However, these cells were not activated, but had reduced levels of TCR and CD5. Moreover, they produced lower cytokine amounts and showed faster dephosphorylation of linker for activation of T cells and ERK upon activation. Normal TCR levels and cytokine production were restored by culturing cells in the absence of TCR/spMHC interaction, demonstrating dynamic tuning of peripheral T cell responses. The effect of avidity for self-ligand(s) on this sensory adaptation was studied by expressing ZAP-YEEI in P14 or HY TCR transgenic backgrounds. Unexpectedly, double-transgenic animals expressed ZAP-YEEI prematurely in double-positive thymocytes, but no overt alteration of selection processes was observed. Instead, modifications of TCR and CD5 expression due to ZAP-YEEI suggested that signal tuning occurred during thymic maturation. Importantly, although P14 X ZAP-YEEI peripheral CD8 T cells were reduced in number and showed lower Ag-induced cytokine production and limited lymphopenia-driven proliferation, the peripheral survival/ expansion and Ag responsiveness of HY X ZAP-YEEI cells were enhanced. Our data provide support for central and peripheral sensory T cell adaptation induced as a function of TCR avidity for self-ligands and signaling level. This may contribute to buffer excessive autoreactivity while optimizing TCR repertoire usage.