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

• 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
• 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

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）：由于记忆T细胞的频率升高、自我更新能力强以及重新激活后快速获得效应功能，记忆T细胞具有增强的抵御二次攻击的能力，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，细胞内病原体急性感染后效应和记忆 CD4+ T 细胞的分化在关键方面与 CD8+ T 细胞的分化不同。特别是，招募 CD8+ T 细胞进入免疫反应的事件也足以实现所有后续分化阶段，包括效应分化和记忆分化。另一方面，CD4+ T 细胞经历渐进的分化阶段。与 CD8+ T 细胞相比，它们还需要更长的刺激期才能经历强劲的初级和次级扩增。我们最近发现，免疫反应中的一些 CD4+ T 细胞克隆可以经历强劲的扩增和效应分化的测量，但无法填充记忆池。与其他 CD4+ T 细胞应答者相比，这种失败对应于较低的 TCR 亲合力和较高的促凋亡分子 Bim 表达。此外，我们还观察到，虽然 CD4+ 记忆 T 细胞群随着时间的推移而减少，但最长寿的克隆保持了对抗原的最高功能亲和力（定义为响应抗原浓度降低而产生 IFN3 的能力）。这些结果提出了一个模型，其中增加的 TCR 信号促进 CD4+ T 细胞的分层分化，逐步驱动克隆扩张、效应分化、记忆分化，最后驱动能够稳定、长期持续的记忆群体的分化。虽然之前的研究表明高亲和力 TCR 与抗原的相互作用在选择 CD4+ 效应 T 细胞应答者中发挥作用，但我们将尝试定义这些相互作用在选择 CD4+ 记忆 T 细胞群以及刺激稳健的次级反应中所发挥的作用。为此，我们将对 CD4+ 效应子和记忆群体在急性感染反应中的 TCR 库进行全面表征。我们将进一步明确促凋亡介质 Bim 在选择高 TCR 亲合力 CD4+ 记忆 T 细胞库中的作用。从广义上讲，我们将检验这样的假设：随着初次反应期间抗原信号的增加，CD4+ T 细胞经历分化的分层阶段，最强的信号导致稳定的 CD4+ 记忆 T 细胞群。 公共健康相关性：记忆 T 细胞的诱导是免疫系统提供保护以免受先前遇到的传染性病原体侵害的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存活和保护的 CD4+ 记忆 T 细胞的要求。了解这些要求是设计更有效的疫苗接种和免疫治疗策略的先决条件，这些策略旨在诱导 CD4+ T 细胞介导的保护性免疫，特别是与需要更有效疫苗的疾病相关，例如艾滋病、疟疾、结核病和癌症。