Defining the role of microRNAs in CD8 T cell exhaustion

 描述(申请人提供)：持续的病毒感染，包括艾滋病毒、乙肝和丙型肝炎是全球发病率和死亡率的主要原因。尽管我们在使用抗微生物制剂和疫苗治疗急性感染方面取得了成功，但持续的病毒感染会导致相当大的疾病。对慢性病毒感染作出反应的CD8T细胞功能失调，这种状态被称为“衰竭”。转录图谱揭示了对T细胞耗竭生物学的重要见解，包括识别关键的转录因子，以及免疫调节通路，如在控制T细胞耗竭方面起主要作用的PD-1和LAG-3。这些后一种发现导致了非常有希望的治疗慢性病的临床试验 传染病和癌症。尽管取得了这些进展，但CD8 T细胞耗竭的分子机制仍不完全清楚。具体地说，到目前为止，我们对T细胞耗竭的基因表达程序的了解仅限于编码蛋白质的mRNA。在过去的十年中，非编码RNA，特别是microRNAs(MiRs)被认为是细胞发育、分化和功能的关键调节因子。然而，MIR在其中的作用 对感染的免疫力才刚刚开始被揭示，特别是在慢性病毒感染期间，miRs在调节CD8T细胞耗尽方面的作用尚不清楚。我们的初步数据表明，miR-155和其他miR与记忆和疲惫的CD8 T细胞之间的差异有关，但这些非编码RNA如何调控T细胞耗竭的确切方式尚不清楚。因此，我们假设特定的miR，包括miR-155，调节功能记忆和耗尽的CD8T细胞之间蛋白质编码基因的分化、功能和转录的差异。为了验证这一假说，我们提出：目的1.研究miR-155在慢性病毒感染中的作用。我们将通过操纵miR-155的表达来测试这种miR如何在慢性病毒感染期间调节耗尽的CD8T细胞的发育和/或持久性。目的2.寻找在慢性病毒感染过程中调节CD8 T细胞耗竭的新的miRs。我们将测试新的差异表达的miRs在调节疲劳和记忆中的作用。以PD-1和其他抑制受体为靶点来调节T细胞耗竭的临床方法在癌症和慢性感染的治疗中具有很高的前景。然而，由于有效率在10%-50%之间，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的临床方法的迅速发展，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.