Immunobiology of NKT cell development and function

描述（由申请人提供）：不变的自然杀伤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CD 1d限制性细胞已被证明可以积极和消极地调节免疫应答。iNKT细胞的作用范围从对抗肿瘤到抑制或治愈各种自身免疫性疾病。所述细胞具有使其不同于常规T细胞的许多特征，包括其在初级活化后释放大量细胞因子的能力、高度受限的TCR库、活化或记忆表型、NK细胞典型的受体表达和在外周组织中的不均匀分布，仅举几例。iNKT细胞在胸腺中发育的有力证据最近才得到证实。关于这些细胞的早期发育知之甚少，除了它似乎与传统的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的分析到下游信号传导事件的研究，以了解并潜在地操纵这些细胞的发育。我们将首先描述iNKTCR与CD 1d的不寻常相互作用的特性，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。在目的2中，我们提出分析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我们认为iNKT细胞发育所需的第二种受体。这项工作还将通过控制iNKT细胞在胸腺中的发育来调节它们的功能。最后，在目标3中，我们将开发一种方法来标记发育中的iNKT细胞，可能在TCR的细胞表面表达之前。这种方法将为我们提供一种工具来表征和探索iNKT细胞发育的机制。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最终将使人们有可能使用基因治疗方法改变这些细胞的功能，以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.