Immunobiology of NKT cell development and function

描述（由申请人提供）：不变自然杀伤T细胞（iNKT细胞）是一种罕见但有效的细胞群，表达与自然杀伤细胞和T细胞共同的特征。这些CD1d限制性细胞已被证明可以正向和负向调节免疫反应。iNKT细胞的作用范围从对抗肿瘤到抑制或治疗各种自身免疫性疾病。这些细胞具有许多特征，使它们与传统的T细胞不同，包括它们在初级激活后释放大量细胞因子的能力，高度受限的TCR库，激活或记忆表型，NK细胞典型受体的表达以及在外周组织中的不均匀分布，等等。iNKT细胞在胸腺中发育的确切证据直到最近才被确立。人们对这些细胞的早期发育知之甚少，只知道它似乎与传统的T细胞发育不同。我们建议研究iNKT细胞发育的几个方面，从TCR的分析到下游信号事件的研究，以努力理解和潜在地操纵这些细胞的发育。我们将首先描述iNKTCR与CD1d不寻常的相互作用的特性，以了解这种非常强的tcr -配体相互作用的生物学如何帮助定义iNKT细胞的功能。在Aim 2中，我们建议分析src家族蛋白激酶Fyn在iNKT细胞发育中的关键和可能独特的功能。Fyn的研究将指导我们寻找iNKT细胞发育所需的第二种受体。这项工作还将寻求通过控制胸腺中iNKT细胞的发育来调节其功能。最后，在Aim 3中，我们将开发一种方法来标记发育中的iNKT细胞，在它们发育的早期，可能在细胞表面表达TCR之前。这种方法将为我们提供表征和探索iNKT细胞发育机制的工具。总的来说，这些研究将有助于我们对iNKT细胞生物学的几个关键方面的基本理解。了解iNKT细胞发育的关键方面将最终使利用基因治疗方法改变这些细胞的功能成为可能，从而控制癌症和其他疾病。

DESCRIPTION (provided by applicant): 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.