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

描述（由申请人提供）：由于其频率升高、自我更新能力和再激活后快速获得效应子功能，记忆T细胞具有增强的保护免受二次攻击的能力，并且其产生是许多疫苗策略的焦点。然而，最近的研究表明，在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细胞不同。特别是，将CD8+ T细胞募集到免疫应答中的事件也足以使所有后续分化阶段成为可能，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来经历稳健的初次和二次扩增。我们最近发现，免疫应答中的一些CD4+ T细胞克隆可以经历稳健的扩增和效应分化的测量，但不能填充记忆池。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细胞群随时间下降，但最长寿的克隆保持了对抗原的最高功能亲合力（如通过响应于抗原浓度降低而产生IFN 3的能力所定义的）。这些结果提示了一种模型，其中增加的TCR信号促进CD4+ T细胞的分级分化，逐渐驱动克隆扩增、效应分化、记忆分化以及最终能够稳定、长期持续的记忆群体的分化。虽然以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细胞群体以及刺激稳健的次级应答中所起的作用。为了做到这一点，我们将进行一个彻底的表征的TCR库的CD4+效应和记忆人口在急性感染的反应。我们将进一步说明促凋亡介质Bim在选择高TCR亲合力CD4+记忆T细胞库中的作用。广义上，我们将测试的假设，即抗原信号增加，在初级反应，CD4+ T细胞经历分化的分级阶段，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提供保护免受先前遇到的感染性病原体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。理解这些要求是设计更有效的疫苗接种和免疫策略的先决条件，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，如艾滋病、疟疾、结核病和癌症有关。

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.