Regulation of NKT cell development and function by c-Myb

描述(申请人提供)：NKT细胞代表一个独特的T淋巴细胞亚群，识别非经典MHC I类分子CD1d提出的糖脂抗原。NKT细胞对抗原的识别导致了一场“细胞因子风暴”；在数小时内，大量Th1和Th2细胞因子和趋化因子的分泌，让人想起先天功能，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个T细胞、树突状细胞和中性粒细胞，并参与包括微生物免疫和肿瘤排斥在内的多个过程。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发挥了作用。我们的结果表明，c-Myb转录因子在NKT细胞的发育中起着关键作用，它在造血过程中起着多种作用。在阳性选择之前，DP胸腺细胞中c-Myb的可诱导缺失导致NKT细胞发育完全受阻。初步证据表明，不同的机制可能对这种影响负责。C-Myb：胸腺细胞半衰期缩短，TcR1重排缺陷--可能继发于半衰期缺陷--以及NKT细胞阳性选择所需的SLAM/SAP信号通路成员表达缺陷。在这项资助的目的之一，我们提议进行实验，详细分析这些机制对c-Myb的最终表型的贡献：胸腺细胞。在第二个目标中，我们将从成熟的NKT细胞中删除c-Myb，并分析其对成熟NKT细胞的动态平衡和功能的贡献。 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反应中发挥重要作用。它们功能的改变可能在自身免疫性疾病的发病机制中发挥作用，如狼疮或糖尿病，以及动脉粥样硬化。该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为疾病期间对它们的操纵提供线索。

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.