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

描述(申请人提供)：由于记忆T细胞的频率提高、自我更新的能力以及在重新激活后迅速获得效应器功能，因此具有增强的保护二次攻击的能力，它们的产生是许多疫苗策略的重点。然而，最近的研究表明，急性细胞内感染后效应性和记忆性CD4+T细胞的分化在关键方面不同于CD8+T细胞。特别是，将CD8+T细胞招募到免疫反应中的事件也足以使所有后续的分化阶段，包括效应器和记忆分化。另一方面，CD4+T细胞经历了逐渐分化的阶段。与CD8+T细胞相比，它们还需要更长的刺激期来经历强劲的一次和二次扩增。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张和一定程度的效应器分化，但无法填充内存池。这一失败对应于TCR亲和力较低，与其他CD4+T细胞反应者相比，促凋亡分子Bim的表达较高。此外，我们还观察到，虽然CD4+记忆T细胞数量随着时间的推移而下降，但最长寿的克隆保持了对抗原的最高功能亲和力(根据对抗原浓度下降的反应产生IFN3的能力)。这些结果提示了一种模型，在该模型中，增加的TCR信号促进了CD4+T细胞的分级分化，逐步推动克隆扩张、效应器分化、记忆分化，最后是能够稳定、长期持续的记忆群体的分化。虽然先前的研究表明TCR与抗原的高亲和力相互作用在选择CD4+效应T细胞反应者中起作用，但我们将尝试确定这些相互作用在选择CD4+记忆性T细胞群体以及刺激强大的次级反应中所起的作用。为了做到这一点，我们将对急性感染反应中的CD4+效应器和记忆群体的TCR谱系进行彻底的表征。我们将进一步明确促凋亡介质Bim在选择高TCR亲和力的CD4+记忆性T细胞谱系中的作用。广泛地说，我们将检验这一假设，即随着抗原信号在最初的反应中增加，CD4+T细胞经历分级分化阶段，最强的信号导致稳定的CD4+记忆T细胞群。 公共卫生相关性：记忆T细胞的诱导是免疫系统针对以前遇到的传染性病原体提供保护的能力的基本组成部分。在这个项目中，我们将探索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战略的先决条件，目的是诱导CD4+T细胞介导的保护性免疫，特别是与艾滋病、疟疾、结核病和癌症等需要更有效疫苗的疾病有关。

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.