REGULATION OF LYMPHOCYTE PROLIFERATION AND CELL CYCLE PROGRESSION

淋巴细胞增殖和细胞周期进展的调节

• 批准号: 2463800
• 负责人: R J HODES
• 金额: --
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/2463800
• 关键词: DNA directed DNA polymerase; cell cycle; cell differentiation; enzyme activity; enzyme induction /repression; helper T lymphocyte; human tissue; immunogenetics; immunologic memory; immunoregulation; leukopoiesis; lymphocyte proliferation; restriction fragment length polymorphism; restriction mapping; telomerase; telomere

The replicative history and replicative potential of human naive and memory T cells, critical parameters of lymphocyte biology, were analyzed. Telomeres are unique terminal chromosomal structures which shorten with cell division in vitro and with increased age in vivo for human somatic cells. We assessed telomere length as a measure of the in vivo replicative history of naive and memory human T cells, and found that telomeric terminal restriction fragments were 1.4 0.1 kb longer in CD4+ naive T cells than in memory cells from the same donors, a relationship that was constant over a wide range of donor age. This suggests that the differentiation of memory cells from naive precursors occurs with substantial clonal expansion that is similar over a wide age range. The in vitro replicative capacity of naive cells was 128-fold greater than that of memory cells from the same donors. Human CD4+ naive and memory cells thus differ in in vivo replicative history as reflected in telomeric length as well as in their residual replicative capacity. These relationships may be significant for pathologies such as HIV infection, in which CD4+ T cell generation may be compromised, and for therapeutic interventions mediated by cells whose in vivo expansion is essential for therapeutic effect. Telomerase, a ribonucleoprotein that is capable of synthesizing telomeric repeats, is expressed in germline and malignant cells and is absent in most normal human somatic cells. The selective expression of telomerase has thus been proposed to be a basis for the immortality of the germline and of malignant cells. When telomerase activity was analyzed in normal human T lymphocytes, it was found that telomerase is expressed at a high level in thymocytes, at an intermediate level in tonsil T cells, and at a low to undetectable level in peripheral blood T cells. Moreover, telomerase activity was highly inducible in peripheral T lymphocytes by activation through CD3 and CD28 (anti-CD3/CD28). Telomerase may thus play a permissive role in T cell development and in determining the capacity of lymphoid cells for clonal expansion.

人类天真的复制历史和复制潜力 记忆 T 细胞是淋巴细胞生物学的关键参数 分析了。 端粒是独特的末端染色体结构 在体外随着细胞分裂而缩短，在体内随着年龄的增加而缩短 人类体细胞。 我们评估端粒长度作为衡量 人类幼稚T细胞和记忆T细胞的体内复制历史，并发现 端粒末端限制性片段长 1.4 0.1 kb CD4+ 初始 T 细胞与来自同一供体的记忆细胞相比， 这种关系在广泛的捐赠者年龄范围内保持不变。 这 表明记忆细胞与幼稚前体细胞的分化 伴随着大量的克隆扩增而发生，这种扩增在整个年龄范围内都是相似的 范围。 幼稚细胞的体外复制能力是原来的128倍 大于来自相同供体的记忆细胞。 人类 CD4+ 幼稚 因此，记忆细胞在体内复制历史上有所不同，这反映了 端粒长度及其剩余复制能力。 这些关系对于艾滋病毒等疾病可能具有重要意义 感染，其中 CD4+ T 细胞的生成可能受到损害，并且对于 由体内扩增的细胞介导的治疗干预 对于治疗效果至关重要。 端粒酶，一种核糖核蛋白，能够合成 端粒重复序列在生殖细胞和恶性细胞中表达， 大多数正常人体细胞中不存在。 的选择性表达 因此，端粒酶被认为是人类永生的基础。 生殖细胞和恶性细胞。 当分析端粒酶活性时 正常人T淋巴细胞中，发现端粒酶表达于 胸腺细胞中水平较高，扁桃体 T 细胞中水平中等， 外周血 T 细胞的水平低至无法检测到。 而且， 端粒酶活性在外周T淋巴细胞中被高度诱导 通过 CD3 和 CD28 激活（抗 CD3/CD28）。 端粒酶可能因此发挥作用 在 T 细胞发育和决定 T 细胞能力方面发挥许可作用 用于克隆扩增的淋巴细胞。