NKT cells: Novel Protective T cells against malaria

描述（由申请人提供）：自然杀伤T（NKT）细胞，最少 已知的T细胞群，代表了大部分的T细胞 存在于小鼠和人类的肝脏中。小鼠NKT细胞表达NK标记物 1），并且在大多数情况下，由NK1.1编码的单一不变T细胞受体， Va 14和Ja 281基因片段。最近，合成糖脂， α-半乳糖神经酰胺（aGalCer）在这种情况下显示激活NKT细胞。 CD 1分子。 我早期的研究表明，aGalCer显示出强大的抗寄生虫 效果，通过消除 寄生虫的肝脏阶段发现aGalCer的这种抗寄生虫活性 由Va 14 NKT细胞介导，因为Va 14 NKT缺陷，以及 CD 1缺陷小鼠也缺乏NKT细胞，无法产生保护作用 对疟疾的抵抗作用。最近，我们的初步研究 已经表明aGalCer增强了由以下引起的保护性抗疟疾免疫力： 用辐射的子孢子免疫。这些初步数据进一步 表明约氏疟原虫血液提取物的不溶性部分 阶段激活野生型肝淋巴样细胞，但不激活NKT缺陷型肝淋巴样细胞， CD id突变小鼠。 本研究提案的总体目标是进一步表征和 确定NKT细胞在抗疟疾免疫反应中的作用 对小鼠为此，我计划：1）界定疟疾的性质特异性 通过aGalCer激活的NKT细胞增强的免疫应答，并确定其 在疟疾免疫小鼠中的持续时间; 2）通过以下方法确定机制： 所述aGalCer活化的NKT细胞增强保护性抗疟疾免疫， 相应的特异性T细胞反应; 3）鉴定和表征 激活NKT细胞的寄生虫衍生抗原。 这些研究有望提供有关NKT细胞 自然免疫和后天免疫之间的区别。我们的发现可能是 不仅适用于疟疾，也适用于其他细胞内微生物， 病原体此外，由于aGalCer不仅刺激鼠而且刺激人， NKT细胞，我们的研究所获得的知识有望有助于 了解人类NKT细胞的作用，并设计新的，更 高效疫苗

DESCRIPTION (provided by applicant): Natural killer T (NKT) cells, the least known population of T cells, represent a large proportion of the T cells present in the liver of mice and humans. Murine NKT cells express the NK marker (NK1.l) and, in most instances, a single invariant T cell receptor encoded by the Va14 and Ja281 gene segments. Most recently, a synthetic glycolipid, a-galactosylceramide (aGalCer), was shown to activate NKT cells in the context of CD1 molecules. My earlier studies demonstrated that aGalCer displayed a strong anti-parasitic effect, preventing mice from developing overt malaria infection by eliminating the parasite's liver stages. This anti-parasitic activity of aGalCer was found to be mediated by Va14 NKT cells, since Va14 NKT-deficient, as well as CD1-deficient mice, which also lack NKT cells, fail to develop protection against malaria upon aGalCer injection. More recently, our preliminary studies have shown that aGalCer enhances protective anti-malaria immunity elicited by immunization with irradiated sporozoites. These preliminary data further indicate that the insoluble fraction of extracts from Plasmodium yoelii blood stages activates liver lymphoid cells of wild type, but not of NKT-deficient, CD id-mutant mice. The overall aim of this research proposal is to further characterize and determine the role that NKT cells play in the immune response against malaria in mice. For this purpose, I plan to: 1) Define the nature of malaria-specific immune responses enhanced by aGalCer-activated NKT cells, and determine their time of persistence in malaria-immunized mice; 2) Determine the mechanisms by which aGalCer-activated NKT cells enhance protective anti-malaria immunity and the corresponding specific T cell responses; 3) Identify and characterize parasite-derived antigen(s) that activate NKT cells. These studies are expected to provide information on the link that NKT cells establish between natural and acquired immunity. Our findings might be applicable not only to malaria, but also to other intra-cellular microbial pathogens. Furthermore, since aGalCer not only stimulates murine but also human NKT cells, the knowledge obtained by our studies is expected to contribute to the understanding of the role of human NKT cells, and the design of novel, more efficient vaccines.