Defining the role of microRNAs in CD8 T cell exhaustion

 描述（由申请方提供）：持续性病毒感染，包括HIV、B型和C型肝炎，是全球发病率和死亡率的主要原因。尽管我们使用抗微生物剂和疫苗在急性感染方面取得了成功，但持续的病毒感染会引起相当大的疾病。响应慢性病毒感染的CD 8 T细胞变得功能失调，这种状态称为“衰竭”。mRNA的转录谱揭示了对T细胞耗竭生物学的重要见解，包括鉴定关键转录因子以及免疫调节途径，如PD-1和LAG-3，它们在控制T细胞耗竭中起主要作用。后一项发现导致了非常有希望的治疗慢性 传染病和癌症。尽管有这些进展，CD 8 T细胞耗竭的分子机制仍然不完全确定。具体来说，我们对T细胞耗竭的基因表达程序的理解迄今为止仅限于编码蛋白质的mRNA。在过去的十年中，非编码RNA，特别是microRNA（miRs）已被确定为细胞发育，分化和功能的关键调节因子。然而，miR在 对感染的免疫性仅仅开始被揭示，具体地说，miR在慢性病毒感染期间调节CD 8 T细胞耗竭中的作用是未知的。我们的初步数据表明，miR-155和其他miR与记忆和耗尽的CD 8 T细胞之间的差异有关，但这些非编码RNA如何调节T细胞耗尽尚不清楚。因此，我们假设特定的miR，包括miR-155，调节功能记忆和耗尽的CD 8 T细胞之间的分化，功能和蛋白质编码基因的转录差异。为了验证这一假设，我们提出：目标1。探讨miR-155在慢性病毒感染中的作用。我们将操纵miR-155表达，以测试该miR如何调节慢性病毒感染期间耗尽的CD 8 T细胞的发育和/或持续性。目标二。鉴定在慢性病毒感染期间调节CD 8 T细胞耗竭的新型miR。我们将测试新的差异表达的miR在调节耗竭和记忆中的作用。基于靶向PD-1和其他抑制性受体调节T细胞耗竭的临床方法对于治疗癌症和慢性感染非常有希望。然而，由于疗效范围为10- 50%，显然需要其他方法和对T细胞耗竭的更深入了解。随着调节miR的临床方法的快速发展，拟议的研究将为未来基于miR的感染和癌症治疗进展提供基础。

 DESCRIPTION (provided by applicant): Persistent viral infections, including HIV, hepatitis B and C are major causes of morbidity and mortality worldwide. Despite our successes with acute infections using anti-microbial agents and vaccines, persisting viral infections cause considerable disease. CD8 T cells responding to chronic viral infections become dysfunctional, a state termed "exhaustion". Transcriptional profiling of mRNA has revealed major insights into the biology of T cell exhaustion including the identification of key transcription factors, as wellas immunoregulatory pathways, such as PD-1 and LAG-3 that have major roles in controlling T cell exhaustion. These latter findings have led to highly promising clinical trials for treating chronic infectious diseases and cancer. Despite these advances, the molecular mechanisms of CD8 T cell exhaustion remain incompletely defined. Specifically, our understanding of the gene expression program of T cell exhaustion has been limited so far to only protein-coding mRNA. In the past decade, non-coding RNAs and especially microRNAs (miRs) have been identified as crucial regulators of cell development, differentiation, and function. However, the role of miRs in immunity to infection is only beginning to be revealed and specifically the role of miRs in regulating CD8 T cell exhaustion during chronic viral infection is unknown. Our preliminary data indicate that miR-155 and other miRs are associated with differences between memory and exhausted CD8 T cells, but precisely how these non-coding RNAs regulate T cell exhaustion is unclear. Thus, we hypothesize that specific miRs, including miR-155, regulate the differences in differentiation, function and transcription of protein coding genes between functional memory and exhausted CD8 T cells. To test this hypothesis we propose: Aim 1. To investigate the role of miR-155 in chronic viral infection. We will manipulate miR-155 expression to test how this miR regulates the development and/or persistence of exhausted CD8 T cells during chronic viral infection. Aim 2. To identify novel miRs regulating CD8 T cell exhaustion during chronic viral infections. We will test the role of novel differentially expressed miRs in regulating exhaustion v memory. Clinical approaches to modulate T cell exhaustion based on targeting PD-1 and other inhibitory receptors are highly promising for the treatment of cancer and chronic infections. However, with efficacy ranging from 10- 50%, other approaches and a deeper understanding of T cell exhaustion is clearly warranted. With clinical approaches to modulate miRs rapidly developing, the proposed studies will provide a foundation for future miR-based therapeutic advances in infection and cancer.