Marquez Maria-Elena, Ellmeier Wilfried, Sanchez-Guajardo Vanesa, Freitas Antonio A, Acuto Oreste, Di Bartolo Vincenzo
Molecular Immunology Unit, Department of Immunology, Institut Pasteur, Paris, France.
J Immunol. 2005 Dec 1;175(11):7388-97. doi: 10.4049/jimmunol.175.11.7388.
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.
T细胞激活阈值的适应性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情况，我们构建了一种转基因小鼠模型，通过在分选后的CD8胸腺细胞和T细胞中表达Zap70功能获得性突变体（ZAP-YEEI）来增加TCR依赖性兴奋性。在携带ZAP-YEEI的CD8 T细胞中检测到T细胞激活的Zap70底物接头的基础磷酸化增加。然而，这些细胞并未被激活，而是TCR和CD5水平降低。此外，它们产生的细胞因子量较低，并且在激活后T细胞激活接头和ERK的去磷酸化速度更快。在没有TCR/spMHC相互作用的情况下培养细胞可恢复正常的TCR水平和细胞因子产生，这表明外周T细胞反应存在动态调节。通过在P14或HY TCR转基因背景中表达ZAP-YEEI，研究了对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，但未观察到选择过程的明显改变。相反，ZAP-YEEI导致的TCR和CD5表达的改变表明信号调节发生在胸腺成熟过程中。重要的是，尽管P14×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×ZAP-YEEI细胞的外周存活/扩增和Ag反应性增强。我们的数据为作为TCR对自身配体的亲和力和信号水平的函数诱导的中枢和外周感觉T细胞适应提供了支持。这可能有助于缓冲过度的自身反应性，同时优化TCR库的使用。
