Firpo Eduardo J, Kong Raymond K, Zhou Qinghong, Rudensky Alexander Y, Roberts James M, Franza B Robert
Cell Systems Initiative, Department of Bioengineering, Howard Hughes Medical Institute, School of Medicine, University of Washington, Seattle, WA 98195, USA.
Immunology. 2002 Dec;107(4):480-8. doi: 10.1046/j.1365-2567.2002.01540.x.
The transgenic T-cell receptor in mouse TEa CD4+ lymphocytes recognizes an endogenous peptide, Ealpha52-68, presented in the context of the major histocompatibility complex class II molecule I-Ab. In response to an optimal peptide concentration TEa cells enter the cell cycle and proliferate. However, a single exposure to high doses of the specific peptide diminished cell expansion upon subsequent restimulation. This hyporesponsive, or anergic, phenotype can still be detected after multiple restimulations indicating that the hyporesponsiveness persists despite cell division and it was inherited by daughter cells. Furthermore, we demonstrated that this hypoproliferative response is associated with high p27Kip1 and cyclin E protein levels, and reduced intracellular interleukin-2 (IL-2) expression. Addition of exogenous IL-2 was required to reset p27Kip1 levels in the progeny derived from hyporesponsive TEa cells. Thus, we have established antigen dose-dependent induction of a reversible, inheritable (i.e. epigenetic) phenotype and we have identified at least three components of the network of interactions: p27Kip1 cyclin E, and IL-2 expression.
小鼠TEa CD4+淋巴细胞中的转基因T细胞受体识别在主要组织相容性复合体II类分子I-Ab背景下呈递的内源性肽Ealpha52-68。在最佳肽浓度刺激下，TEa细胞进入细胞周期并增殖。然而，单次暴露于高剂量的特异性肽会在随后的再刺激时减少细胞扩增。这种低反应性或无反应性表型在多次再刺激后仍可检测到，这表明尽管细胞分裂，但低反应性仍然持续存在，并且由子细胞继承。此外，我们证明这种低增殖反应与高p27Kip1和细胞周期蛋白E蛋白水平以及细胞内白细胞介素-2（IL-2）表达降低有关。需要添加外源性IL-2来重置低反应性TEa细胞后代中的p27Kip1水平。因此，我们建立了抗原剂量依赖性诱导的可逆、可遗传（即表观遗传）表型，并且我们已经确定了相互作用网络的至少三个组成部分：p27Kip1、细胞周期蛋白E和IL-2表达。
