Itk mediated tuning of CD8+ memory T cell development

Itk 介导的 CD8 记忆 T 细胞发育调节

• 批准号: 9303296
• 负责人: Avery August
• 金额: $ 38.15万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-24 至 2020-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9303296
• 关键词: Affect; Affinity; Antigens; Avidity; Bacteria; Bacterial Infections; CD8-Positive T-Lymphocytes; CD8B1 gene; Cessation of life; Clonal Expansion; Data; Development; Effector Cell; Generations; Goals; Human; Immune response; Immunologic Memory; Infection; Inflammation; Interferon Type II; Lead; Mediating; Memory; Methods; Molecular; Pathway interactions; Pharmacologic Substance; Phase; Play; Process; Production; Protein Tyrosine Kinase; Receptor Signaling; Role; Shapes; Signal Pathway; Signal Transduction; T cell differentiation; T cell response; T memory cell; T-Cell Development; T-Cell Receptor; T-Lymphocyte; Testing; Therapeutic; Vaccination; Vaccines; Work; experimental study; follow-up; inflammatory milieu; innovation; long term memory; novel strategies; pathogen; public health relevance; receptor; response; transcriptome; vaccine efficacy; virus development

 DESCRIPTION (provided by applicant): Abstract Vaccine efficacy depends on strong long-term development of immune memory. CD8+ T cells play critical roles in the immune response to bacteria and viruses, and the development of an effective CD8+ T cell immune response has been intensely investigated. Memory CD8+ T cells develop following antigenic responses over several identifiable phases. Initial antigen or pathogen recognition initiates clonal expansion of naïve T cells, which develop into effector T cells. Upon pathogen or antigen clearance, these effector T cells undergo a drastic contraction phase, with death of a majority of the effector cell, and the development of memory precursor effector cells, which proceed to differentiate into memory T cells. Methods to selectively manipulate this process would greatly enhance tuning the immune response in specific conditions. However, this process is still poorly understood. Three parameters that affect these responses are antigen affinity, T cell receptor (TcR) signal strength and inflammation. Antigen affinity (for TcR) and TcR signal are T cell intrinsic, while inflammation is thought to be T cell extrinsic. How these three parameters intersect to control memory development is unclear. The tyrosine kinase Itk is a pharmaceutically tractable target that regulates TcR signal strength, and our preliminary data suggest that it tunes T cell mediated inflammation, and timing of the development CD8+ memory T cell response. The objective of this application is to determine the role of Itk regulated TcR signal strength and antigen affinity for TcR, in tuning the development of CD8+ effector and memory responses during bacterial infection. We will test the hypothesis that pathways regulated by Itk tune inflammation during CD8+ T cell response, regulating the development of memory CD8+ T cells in response to infection. Our specific aims are: 1) Determine the ability of TCR signal strength to tune antigen affinity induced development of short-term effector and long term memory CD8+ T cells during infection; 2) Determine the mechanism by which of Itk regulates development of MPEC during infection induced memory generation, and 3) Determine the ability of Itk to tune inflammation and thus the development of short-term effector and long-term memory CD8+ T cells during infection. This work is extremely innovative as we have exciting preliminary data that when fleshed out, will provide information on a signaling pathway that could be manipulated to enhance the development of memory T cells, while reducing vaccine induced inflammation. This work is also innovative because we have devised novel approaches to study the impact of this signaling pathway on the development of different phases of the CD8+ T cell response. Furthermore, our work is highly translatable as it could lead to a method to tune the development of CD8+ T cell memory in humans.

 描述（由申请人提供）：摘要疫苗效力取决于免疫记忆的长期发展。CD 8 + T细胞在对细菌和病毒的免疫应答中起着关键作用，并且已经深入研究了有效的CD 8 + T细胞免疫应答的发展。记忆性CD 8 + T细胞在几个可识别的阶段中随着抗原应答而发展。初始抗原或病原体识别启动幼稚T细胞的克隆扩增，幼稚T细胞发育成效应T细胞。在病原体或抗原清除后，这些效应T细胞经历剧烈的收缩期，其中大部分效应细胞死亡，并且发育记忆前体效应细胞，其继续分化成记忆T细胞。选择性地操纵该过程的方法将极大地增强在特定条件下调节免疫应答。然而，人们对这一过程仍然知之甚少。影响这些反应的三个参数是抗原亲和力、T细胞受体（TcR）信号强度和炎症。抗原亲和力（对TcR）和TcR信号是T细胞内在的，而炎症被认为是T细胞外在的。这三个参数是如何交叉控制记忆发展的还不清楚。酪氨酸激酶Itk是调节TcR信号强度的药学上易处理的靶点，并且我们的初步数据表明它调节T细胞介导的炎症和发展CD 8+记忆T细胞应答的时间。本申请的目的是确定Itk调节的TcR信号强度和TcR的抗原亲和力在细菌感染期间调节CD 8+效应器和记忆反应的发展中的作用。我们将检验这一假设，即在CD 8 + T细胞应答过程中，Itk调节炎症的途径，调节记忆性CD 8 + T细胞对感染的应答。我们的具体目标是：1）确定TCR信号强度的能力， 调节感染期间抗原亲和力诱导的短期效应和长期记忆CD 8 + T细胞的发育; 2）确定Itk在感染诱导的记忆产生期间调节MPEC发育的机制，和3）确定Itk调节炎症并因此调节感染期间短期效应和长期记忆CD 8 + T细胞发育的能力。这项工作是非常创新的，因为我们有令人兴奋的初步数据，当充实出来时，将提供有关信号通路的信息，可以操纵该信号通路来增强记忆T细胞的发育，同时减少疫苗诱导的炎症。这项工作也是创新的，因为我们设计了新的方法来研究这种信号通路对CD 8 + T细胞反应不同阶段发展的影响。此外，我们的工作是高度可翻译的，因为它可能导致一种方法来调整人类CD 8 + T细胞记忆的发展。