Regulation of NKT cell development and function by c-Myb

描述（由申请方提供）：NKT细胞代表识别由非经典MHC I类分子CD 1d呈递的糖脂抗原的T淋巴细胞的独特亚群。NKT细胞的抗原识别导致“细胞因子风暴”;在数小时内分泌大量Th 1和Th 2细胞因子和趋化因子，使人联想到先天功能而不是适应性功能。通过这种细胞因子和趋化因子的产生，NKT细胞影响免疫系统中许多其他细胞的行为，包括NK细胞，巨噬细胞，其他12 T细胞，树突状细胞和嗜中性粒细胞，并参与多种过程，包括微生物免疫和肿瘤排斥。同样，它们似乎在自身免疫过程、动脉粥样硬化和过敏的发病机制中起作用。 我们的研究结果表明，c-Myb，在造血中发挥多种作用的转录因子，是NKT细胞发育的关键球员。DP胸腺细胞中c-Myb的诱导性缺失导致NKT细胞发育的完全阻断，在阳性选择之前。初步证据表明，不同的机制可能是造成这种影响的原因。c-Myb：胸腺细胞具有缩短的半衰期，具有TcR 1重排缺陷-这可能继发于半衰期缺陷-并且具有NKT细胞阳性选择所需的SLAM/SAP信号传导途径成员表达缺陷。 在本补助金的目的之一，我们提出的实验，详细分析这些机制的最终表型的c-Myb：胸腺细胞的贡献。在目标二中，我们将从成熟NKT细胞中删除c-Myb，并分析其对成熟NKT细胞稳态和功能的贡献。 公共卫生相关性：NKT细胞是淋巴细胞的一个独特亚群，在针对病原体的免疫应答中发挥重要作用。其功能的改变可能在自身免疫性疾病如狼疮或糖尿病以及动脉粥样硬化的发病机制中起作用。 本项目将分析转录因子c-Myb在NKT细胞发育和功能中的作用。更好地了解这些过程可能会提供线索，他们在疾病期间的操纵。

DESCRIPTION (provided by applicant): NKT cells represent a distinct subset of T lymphocytes that recognize glycolipid antigens presented by the nonclassical MHC class I molecule CD1d. Antigen recognition by NKT cells results in a "cytokine storm"; the secretion, within hours, of large quantities of Th1 and Th2 cytokines and chemokines, reminiscent of innate rather than adaptive functions. Through this cytokine and chemokine production, NKT cells influence the behavior of many other cells in the immune system, including NK cells, macrophages, other 12 T cells, dendritic cells and neutrophiles, and have been implicated in multiple processes, including microbial immunity, and tumor rejection. Similarly, they seem to play a role in the pathogenesis of autoimmune processes, atherosclerosis and allergy. Our results demonstrate that c-Myb, a transcription factor that plays multiple roles in hematopoiesis, is a critical player in NKT cell development. Inducible deletion of c-Myb in DP thymocytes results in a complete blockade in NKT cell development, previous to positive selection. Preliminary evidence suggests that different mechanisms may be responsible for this effect. c-Myb: thymocytes have a shortened half-life, have defects in TcR1 rearrangement -that may be secondary to the defect in half-life- and have defects in the expression of members of the SLAM/SAP signaling pathway, which is required for NKT cell positive selection. In aim one of this grant we propose experiments to analyze in detail the contributions of these mechanisms to the final phenotype of c-Myb: thymocytes. In aim two we will delete c-Myb from mature NKT cells and analyze its contribution to mature NKT cell homeostasis and function. PUBLIC HEALTH RELEVANCE: NKT cells are a distinct subset of lymphocytes that play an important role in immune responses against pathogens. Alterations in their function may play a role in the pathogenesis of autoimmune disorders such as lupus or diabetes, as well as in atherosclerosis. This project will analyze the role of c-Myb, a transcription factor, in the development and function of NKT cells. A better understanding of these processes may offer clues to their manipulation during disease.