The role of antigenic stimulatory strength in the selection and differentiation o

抗原刺激强度在选择和分化中的作用

基本信息

批准号：
8212268
负责人：
Matthew A Williams
金额：
$ 37万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-02-01 至 2015-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8212268
关键词：
Acquired Immunodeficiency Syndrome Acute Antigens Apoptosis Apoptotic Automobile Driving Avidity CD4 Positive T Lymphocytes CD8B1 gene Cell Survival Cells Cessation of life Clonal Expansion Disease Dose Drug or chemical Tissue Distribution Effector Cell Epitopes Event Failure Frequencies Generations Growth Factor Immune response Immune system Immunity Immunization Immunotherapeutic agent Infection Investigation Kinetics Left Life Listeria monocytogenes Lymphocytic choriomeningitis virus Maintenance Malaria Malignant Neoplasms Measures Mediating Mediator of activation protein Memory Modeling Peptides Phase Play Population Proteins Recombinants Recruitment Activity Role Shapes Signal Transduction Specific qualifier value Staging Stimulus T cell response T memory cell T-Lymphocyte TCR Activation Testing Time Transgenic Organisms Tuberculosis Up-Regulation Vaccination Vaccines Virus Diseases base cytokine cytotoxic design memory CD4 T lymphocyte novel pathogen public health relevance response self-renewal transcription factor

项目摘要

DESCRIPTION (provided by applicant): Because of their elevated frequency, ability to self-renew and rapid acquisition of effector function following re-activation, memory T cells have an enhanced ability to protect from secondary challenge, and their generation is the focal point of numerous vaccine strategies. However, recent studies have demonstrated that the differentiation of effector and memory CD4+ T cells following acute infection with intracellular pathogens differs in key respects from that of CD8+ T cells. In particular, the events that recruit CD8+ T cells into the immune response are also sufficient to enable all subsequent differentiation stages, including effector and memory differentiation. CD4+ T cells, on the other hand, undergo progressive stages of differentiation. They also require a longer stimulatory period to undergo robust primary and secondary expansion as compared to CD8+ T cells. We have recently found that some CD4+ T cell clones within the immune response can undergo robust expansion and a measure of effector differentiation but fail to populate the memory pool. This failure corresponds to lower TCR avidity and higher expression of the pro-apoptotic molecule Bim as compared to other CD4+ T cell responders. Furthermore, we also observed that while CD4+ memory T cell populations declined over time, the most long-lived clones maintained the highest functional avidity for antigen (as defined by the ability to produce IFN3 in response to decreasing concentrations of antigen). These results suggest a model in which increasing TCR signals promote a hierarchical differentiation of CD4+ T cells, progressively driving clonal expansion, effector differentiation, memory differentiation and finally the differentiation of memory populations capable of stable, long- term persistence. While previous studies have suggested a role for high avidity TCR interactions with antigen in selecting CD4+ effector T cell responders, we will attempt to define the role that these interactions play in the selection of CD4+ memory T cell populations as well as in the stimulation of robust secondary responses. To do this we will undertake a thorough characterization of the TCR repertoire of CD4+ effector and memory populations in the response to acute infection. We will further specify the role of the pro-apoptotic mediator Bim in the selection of high TCR avidity CD4+ memory T cell repertoires. Broadly, we will test the hypothesis that as antigenic signals increase during the primary response, CD4+ T cells undergo hierarchical stages of differentiation, with the strongest signals resulting in stable CD4+ memory T cell populations. PUBLIC HEALTH RELEVANCE: The induction of memory T cells is a fundamental component of the immune system's ability to provide protection from previously encountered infectious pathogens. In this project we will explore the requirements for the establishment of CD4+ memory T cells capable of long-term survival and protection. Understanding these requirements is a pre-requisite to the design of more effective vaccination and immunotherapeutic strategies aimed at inducing CD4+ T cell-mediated protective immunity, with particular relevance to diseases for which more effective vaccines are desirable, such as AIDS, malaria, tuberculosis and cancer.

描述（由申请人提供）：由于其频率升高，自我更新的能力和重新激活后效应子功能的快速获取，记忆T细胞具有增强的保护次要挑战的能力，并且它们的产生是众多疫苗策略的焦点。然而，最近的研究表明，急性感染后效应子和记忆CD4+ T细胞的分化在关键方面与CD8+ T细胞的分化在关键方面有所不同。特别是，将CD8+ T细胞募集到免疫反应的事件也足以使所有随后的分化阶段，包括效应子和记忆分化。另一方面，CD4+ T细胞经历了分化的进行性阶段。与CD8+ T细胞相比，它们还需要更长的刺激时间才能进行稳健的原发性和次要扩张。我们最近发现，免疫反应中的某些CD4+ T细胞克隆可以进行强大的扩展和效应子分化的度量，但无法填充内存池。与其他CD4+ T细胞响应者相比，这种失败对应于较低的TCR亲和力和促凋亡分子BIM的较高表达。此外，我们还观察到，虽然CD4+记忆T细胞种群随着时间的推移而下降，但最长寿的克隆保持了抗原的最高功能亲和力（如响应降低抗原浓度而产生IFN3的能力所定义）。这些结果表明了一个模型，其中增加的TCR信号促进了CD4+ T细胞的分层分化，逐渐推动克隆扩张，效应器分化，记忆分化以及最终的分化能够稳定的长期持久性的记忆种群的分化。尽管先前的研究表明，高潮TCR与抗原在选择CD4+效应T细胞响应者中的作用，但我们将尝试定义这些相互作用在选择CD4+记忆T细胞群体以及刺激可靠的次要反应中所起的作用。为此，我们将在对急性感染的反应中对CD4+效应子和记忆群的TCR曲目进行彻底表征。我们将进一步指定促凋亡介质BIM在选择高TCR亲和力CD4+记忆T细胞库中的作用。从广义上讲，我们将检验以下假设：随着抗原信号在初级响应期间的增加，CD4+ T细胞经历分化的分层阶段，最强的信号导致CD4+记忆T细胞群体稳定。公共卫生相关性：记忆T细胞的诱导是免疫系统提供免受先前遇到的感染性病原体保护能力的基本组成部分。在这个项目中，我们将探讨建立能够长期生存和保护的CD4+记忆T细胞的要求。理解这些要求是设计更有效的疫苗接种和旨在诱导CD4+ T细胞介导的保护性保护性的保护性疫苗和免疫治疗策略的先决条件，与艾滋病，疟疾，疟疾，结核病和癌症等疾病特别相关。