REGULATORY EVENTS IN T CELL DEVELOPMENT IN THE THYMUS

我们的目标是确定重要的分子事件， 胸腺内的T细胞成熟。 在胸腺内，造血 前体细胞经历一系列复杂的发育过程， 成熟的T淋巴细胞能够识别特异性抗原。 这 发育过程似乎是由一系列信号传导引起的， T细胞前体和异质性之间的相互作用， 一组不明确的基质细胞 除了T细胞，还有一类 细胞毒性淋巴细胞被称为“自然杀伤”细胞， 潜在的重要作用，免疫反应，对癌症或 病毒感染的细胞，也可以在胸腺中发育。 我们正在采取 在分子水平上研究胸腺发育的两种方法。 一是 已经建立了一个培养系统，其中第14/15天三阴性 胎儿胸腺细胞可被刺激表达胸腺细胞早期标志物 包括CD 25、ICAM-1和Ly-6A/E。 我们正在研究 激活早期发育步骤的分子信号。 期间 这些研究发现了一种新的前体细胞， T淋巴细胞和自然杀伤细胞。 我们亦得到 一种新的发展途径的证据，允许三阴性 胸腺细胞发育成双阳性胸腺细胞。 第二，我们 创造出基因工程小鼠， （敲除）在胸腺细胞中高度表达的各种基因。 我们目前专注于三个基因： 一种控制Ras成员Rho活性的抑制蛋白 可能参与分子信号级联的家族; ii）Rlk - 酪氨酸激酶的BTK/ITK家族的新描述的成员， 最近与遗传性免疫缺陷状态有关， 参与来自表面抗原受体的信号传导;和iii）Ntk - 一种新描述的与Csk激酶相关的酪氨酸激酶， 通过磷酸化抑制蛋白调节多种Src家族激酶 酪氨酸残基。 由于信号相互作用对于适当的 T细胞分化，这些信号分子的破坏可能 抑制T细胞发育的方式，阐明正常的生理 这些分子的作用。

Our goal has been to define the important molecular events that control T cell maturation within the thymus. Within the thymus, hematopoietic precursor cells undergo a complex set of developmental events and emerge as mature T lymphocytes capable of specific antigen recognition. This developmental process appears to result from a series of signalling interactions between T cell precursors and a heterogeneous and as yet ill-defined set of stromal cells. In addition to T cells, a class of cytotoxic lymphocytes known as "natural killer" cells, which play potentially important roles in immune responses against cancerous or virally-infected cells, can also develop in the thymus. We are taking two approaches to thymic development at the molecular level. First, we have established a culture system in which day 14/15 triple negative fetal thymocytes can be stimulated to express early markers of thymocyte development including CD25, ICAM-1, and Ly-6A/E. We are studying the molecular signals that activate this early developmental step. During these studies we have discovered a novel precursor cell that gives rise to both T lymphocytes and natural killer cells. We have also obtained evidence for a novel developmental pathway that allows triple negative thymocytes to develop into double positive thymocytes. Second, we are creating genetically-engineered mice that are homozygous-deficient (knocked-out) for various genes that are highly expressed in thymocytes. We are currently focusing on three genes: i) Ly-GDI - a GDP-dissociation inhibitor protein that controls the activity of Rho, a member of the Ras family that may be involved in molecular signalling cascades; ii) Rlk - a newly described member of the btk/itk family of tyrosine kinases that have been recently implicated in inherited immunodeficiency states and are involved in signalling from surface antigen receptors; and iii) Ntk - a newly-described tyrosine kinase related to the Csk kinase that regulates various Src family kinases by phosphorylating inhibitory tyrosine residues. Since signalling interactions are critical for proper T cell differentiation, disruption of these signalling molecules may inhibit T cell development in ways that clarify the normal physiological roles of these molecules.