Laboratory of Adaptive Immunity, Institute of Molecular Genetics of the Czech Academy of Sciences, 14220 Prague, Czech Republic.
Department of Biomedicine, University Hospital and University of Basel, 4031 Basel, Switzerland.
Cell Rep. 2020 Feb 4;30(5):1504-1514.e7. doi: 10.1016/j.celrep.2020.01.008.
Overtly self-reactive T cells are removed during thymic selection. However, it has been recently established that T cell self-reactivity promotes protective immune responses. Apparently, the level of self-reactivity of mature T cells must be tightly balanced. Our mathematical model and experimental data show that the dynamic regulation of CD4- and CD8-LCK coupling establish the self-reactivity of the peripheral T cell pool. The stoichiometry of the interaction between CD8 and LCK, but not between CD4 and LCK, substantially increases upon T cell maturation. As a result, peripheral CD8 T cells are more self-reactive than CD4 T cells. The different levels of self-reactivity of mature CD8 and CD4 T cells likely reflect the unique roles of these subsets in immunity. These results indicate that the evolutionary selection pressure tuned the CD4-LCK and CD8-LCK stoichiometries, as they represent the unique parts of the proximal T cell receptor (TCR) signaling pathway, which differ between CD4 and CD8 T cells.
显性自身反应性 T 细胞在胸腺选择过程中被清除。然而，最近已经确定 T 细胞自身反应性可以促进保护性免疫反应。显然，成熟 T 细胞的自身反应性水平必须得到严格平衡。我们的数学模型和实验数据表明，CD4-和 CD8-LCK 偶联的动态调节确立了外周 T 细胞库的自身反应性。CD8 与 LCK 之间的相互作用的化学计量比，而不是 CD4 与 LCK 之间的相互作用的化学计量比，在 T 细胞成熟时显著增加。结果，外周 CD8 T 细胞比 CD4 T 细胞具有更高的自身反应性。成熟的 CD8 和 CD4 T 细胞的不同自身反应性水平可能反映了这些亚群在免疫中的独特作用。这些结果表明，进化选择压力调整了 CD4-LCK 和 CD8-LCK 的化学计量比，因为它们代表了近端 T 细胞受体 (TCR) 信号通路的独特部分，而 CD4 和 CD8 T 细胞之间存在差异。
