REGULATORY EVENTS IN T CELL DEVELOPMENT IN THE THYMUS

我们的目标一直是定义控制的重要分子事件 T细胞在胸腺内成熟。在胸腺内，造血剂 前体细胞经历一系列复杂的发育事件并出现 作为具有特异性抗原识别能力的成熟T淋巴细胞。这 发育过程似乎是一系列信号传递的结果 T细胞前体与异质性和目前为止的相互作用 一组定义不明确的基质细胞。除了T细胞，还有一类 被称为“自然杀手”细胞的细胞毒性淋巴细胞 在抗癌或抗癌免疫反应中的潜在重要作用 病毒感染的细胞，也可以在胸腺中发育。我们要带着 在分子水平上胸腺发育的两种方法。首先，我们 已经建立了一种文化体系，在14/15天三重阴性 胎儿胸腺细胞可被刺激表达胸腺细胞的早期标志 发展包括CD25，ICAM-1和Ly-6A/E。我们正在研究 激活这一早期发育步骤的分子信号。在.期间 这些研究我们发现了一种新的前体细胞，它能产生 对T淋巴细胞和自然杀伤细胞都有影响。我们还获得了 一种允许三重否定的新的发育途径的证据 胸腺细胞发育成双阳性胸腺细胞。第二，我们是 创造纯合子缺陷的基因工程小鼠 (敲除)在胸腺细胞中高表达的各种基因。 我们目前专注于三个基因：i)Ly-GDI-一种GDP-解离 控制Rho活性的抑制蛋白，Rho是RAS的成员 可能参与分子信号级联的家族；ii)Rlk- 一种新发现的BTK/ITK酪氨酸激酶家族成员 最近与遗传性免疫缺陷状态有牵连 参与表面抗原受体的信号传递；以及iii)NTK- 一种与CSK激酶相关的新发现的酪氨酸激酶 通过磷酸化抑制调节各种Src家族的激酶 酪氨酸残留物。由于信令交互对于正确地 T细胞分化，这些信号分子的破坏可能 以阐明正常生理状态的方式抑制T细胞的发育 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.