Immunobiology of NKT cell development and function

不变自然杀伤T细胞(iNKT细胞)是一种罕见但强大的细胞群体，表达的特征是 在自然杀伤细胞和T细胞中都是常见的。这些CD1d限制的细胞已经被展示给两个 积极和消极地调节免疫反应。INKT细胞的作用范围从抗肿瘤到 抑制或治愈各种自身免疫性疾病。这些细胞有许多特征使它们 不同于传统的T细胞，包括它们释放大量细胞因子的能力 初级激活，高度受限的TCR谱系，激活或记忆表型，表达 NK细胞的典型受体，在外周组织中分布不均，仅举几例。 INKT细胞在胸腺发育的确凿证据直到最近才被证实。鲜为人知 关于这些细胞的早期发育，除了它似乎与传统的T细胞不同之外 发展。我们建议研究iNKT细胞发育的几个方面，范围从分析 TCR对下游信号事件的研究，以努力理解并潜在地操纵 这些细胞的发育。我们将首先描述iNKTCR与 CD1d，以了解这种非常强大的TCR-配体相互作用的生物学如何帮助定义 INKT细胞。在目标2中，我们建议分析src家族蛋白的关键和可能独特的功能 激酶、Fyn参与iNKT细胞发育。对Fyn的研究将指导我们寻找拟议的第二个 我们认为iNKT细胞发育所需的受体。这项工作还将寻求调制iNKT细胞 通过控制它们在胸腺中发育的各个方面发挥作用。最后，在目标3中，我们将开发一种方法 标记发育中的iNKT细胞，可能在细胞表面表达 TCR。这种方法将为我们提供一种工具来表征和探索iNKT细胞的潜在机制 发展。 总的来说，这些研究将有助于我们对iNKT细胞的几个关键方面的基本理解 生物学。了解iNKT细胞发育的关键方面最终将使改变 利用基因治疗方法研究这些细胞的功能，以努力控制癌症和其他疾病。

Invariant Natural Killer T cells (iNKT cells) are a rare but potent population of cells expressing features in common with both natural killer cells and T cells. These CD1d restricted cells have been shown to both positively and negatively modulate immune responses. Roles for iNKT cells range from fighting tumors to suppressing or curing various autoimmune diseases. The cells have numerous features that make them distinct from conventional T cells including their ability to release copious amounts of cytokines following primary activation, a highly restricted TCR repertoire, an activated or memory phenotype, expression of receptors typical of NK cells and unequal distribution in peripheral tissues, to name a few. Definitive proof that iNKT cells develop in the thymus has only recently been established. Little is known about the early development of these cells other than that it appears to be distinct from conventional T cell development. We propose to study several aspects of iNKT cell development ranging from an analysis of the TCR to a study of downstream signaling events in an effort to understand and potentially manipulate the development of these cells. We will first characterize properties of the unusual interaction of the iNKTCR with CD1d to learn how the biology of this remarkably strong TCR-ligand interaction helps define the function of iNKT cells. In Aim 2 we propose to analyze the critical and possibly unique function of the Src-family protein kinase, Fyn in iNKT cell development. The studies of Fyn will guide our search for a proposed second receptor that we believe is required for iNKT cell development. This work will also seek to modulate iNKT cell function by controlling aspects of their development in the thymus. Finally, in Aim 3, we will develop a method to tag developing iNKT cells very early in their development, perhaps prior to cell surface expression of the TCR. This approach will give us a tool to characterize and explore the mechanisms underlying iNKT cell development. Overall, these studies will contribute to our basic understanding of several critical aspects of iNKT cell biology. Understanding key aspects of iNKT cell development will eventually make it possible to alter the function of these cells using gene therapy approaches in an effort to control cancer and other diseases.