microRNAs and NKT cell development and function

 描述(申请人提供)：自然杀伤T细胞(NKT)是进化上保守的T细胞亚群，在发育和功能上与传统T细胞不同。NKT细胞能够在激活后迅速分泌大量的各种细胞因子，使其成为多种免疫反应的有力调节者。NKT细胞数量和功能的缺陷与许多疾病的发生有关。然而，在我们对NKT细胞的发育和功能是如何被精确调控的理解上仍然存在着显著的差距。MicroRNAs(MiRNAs)是最近发现的一类进化上保守的非编码小RNA，它负向调节蛋白质编码基因的表达，从而控制必要的生物学功能，促进许多疾病的发生。我们首次报道，在造血过程中，缺失miRNA生物发生的关键酶DICER会导致NKT细胞数量显著减少，NKT细胞成熟和功能受损，而不会改变胸腺中传统的T细胞发育，这表明NKT细胞需要miRNAs。我们的长期目标是了解miRNAs如何调控NKT细胞的发育和功能。虽然有1000多个实验报告了miRNAs，但到目前为止，与NKT细胞相关的特定miRNAs很少。我们的目标是定义特定的miRNAs及其靶点来调控NKT细胞的发育和功能。利用miRNA阵列，我们最近发现了包括miR-155和miR-17-92簇在内的miRNAs在NKT细胞发育和激活过程中的动态表达。这些发现加上我们最近的另一篇报道，导致了我们的中心假设，即这些动态表达的miRNAs是通过微调特定靶基因来控制NKT细胞发育和功能的关键调节因子。在这里，我们将进一步检验这一假设。我们将利用具有miRNA基因获得或丢失的特定miRNA突变小鼠来研究动态和miR-155和miR-17-92表达如何调节NKT细胞的发育和功能。这些研究的结果不仅可能阐明NKT细胞发育的新的免疫学和分子机制，而且可能有助于在NKT细胞治疗的基础上开发新的、更有效的干预策略来治疗自身免疫性疾病、感染和癌症。

 DESCRIPTION (provided by applicant): Natural killer T (NKT) cells are an evolutionarily conserved subset of T cells that are developmentally and functionally distinct from conventional T cells. The ability to quickly secrete large quantities of a variety of cytokines upon activation enables NKT cells to be potent regulators of diverse immune responses. The deficiencies in NKT cell number and function have been linked to the development of many diseases. However, a significant gap remains in our understanding of how the development and function of NKT cells are precisely regulated. MicroRNAs (miRNAs), a recently discovered class of evolutionarily conserved small non-coding RNAs, negatively regulate the expression of protein-coding genes and thereby control essential biological functions and contribute to the development of many diseases. We were the first to report that the deletion of Dicer (a key enzyme for miRNA biogenesis) during hematopoiesis results in a significantly reduced NKT cell number and impaired NKT cell maturation and function, without alternating conventional T cell development in the thymus, suggesting that miRNAs are required for NKT cells. Our long-term goal is to understand how miRNAs regulate NKT cell development and function. While more than 1000 experimentally reported miRNAs, very few specific miRNAs are linked to NKT cells so far. Our objective here is to define specific miRNAs and their targets that regulate NKT cell development and function. Using miRNA arrays, we recently identified dynamic expression of miRNAs, including miR-155, and miR-17-92 cluster, during NKT cell development and activation. These findings plus our recent other report lead to our central hypothesis that these dynamically expressed miRNAs serve as critical regulators controlling NKT cell development and function through fine-tuning of specific target genes. Here we will further test this hypothesis. We will investigate how dynamic and miR-155 and miR-17-92 expression regulates NKT cell development and function using specific miRNA mutant mice with the gain or loss of miRNA gene. The results from proposed studies may not only illuminate the new immunological and molecular mechanisms underlying NKT cell development, but may also facilitate the development of new and more efficient intervention strategies for autoimmune diseases, infection, and cancer based on the NKT cell therapy.