Bird J J, Brown D R, Mullen A C, Moskowitz N H, Mahowald M A, Sider J R, Gajewski T F, Wang C R, Reiner S L
Department of Medicine, Gwen Knapp Center for Lupus and Immunology Research, The University of Chicago, IL 60637, USA.
Immunity. 1998 Aug;9(2):229-37. doi: 10.1016/s1074-7613(00)80605-6.
Helper T (Th) cell differentiation is highly regulated by cytokines but initiated by mitogens. By examining gene expression in discrete generations of dividing cells, we have delineated the relationship between proliferation and differentiation. Initial expression of IL-2 is cell cycle-independent, whereas effector cytokine expression is cell cycle-dependent. IFNgamma expression increases in frequency with successive cell cycles, while IL-4 expression requires three cell divisions. Cell cycle progression and cytokine signaling act in concert to relieve epigenetic repression and can be supplanted by agents that hyperacetylate histones and demethylate DNA. Terminally differentiated cells exhibit stable epigenetic modification and cell cycle-independent gene expression. These data reveal a novel mechanism governing Th cell fate that initially integrates proliferative and differentiative signals and subsequently maintains stability of the differentiated state.
辅助性T（Th）细胞的分化受细胞因子高度调控，但由丝裂原启动。通过检查分裂细胞离散代中的基因表达，我们已经阐明了增殖与分化之间的关系。白细胞介素-2（IL-2）的初始表达与细胞周期无关，而效应细胞因子的表达则依赖于细胞周期。γ干扰素（IFNγ）的表达频率随着连续的细胞周期而增加，而白细胞介素-4（IL-4）的表达需要三次细胞分裂。细胞周期进程和细胞因子信号协同作用以解除表观遗传抑制，并且可以被组蛋白高度乙酰化和DNA去甲基化的试剂所替代。终末分化细胞表现出稳定的表观遗传修饰和与细胞周期无关的基因表达。这些数据揭示了一种控制Th细胞命运的新机制，该机制最初整合增殖和分化信号，随后维持分化状态的稳定性。
