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

描述（由申请人提供）：由于记忆T细胞的频率升高、自我更新能力和在重新激活后快速获得效应功能，记忆T细胞具有增强的保护能力，免受继发性挑战，它们的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，效应和记忆性CD4+ T细胞的分化在关键方面与CD8+ T细胞不同。特别是，招募CD8+ T细胞进入免疫应答的事件也足以启动所有随后的分化阶段，包括效应和记忆分化。另一方面，CD4+ T细胞则经历分化的进行性阶段。与CD8+ T细胞相比，它们还需要更长的刺激期才能经历强劲的原发性和继发性扩张。我们最近发现，免疫反应中的一些CD4+ T细胞克隆可以经历稳健的扩张和一定程度的效应分化，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贪婪度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下降，但寿命最长的克隆对抗原的功能渴望度最高（根据对抗原浓度降低的反应产生IFN3的能力来定义）。这些结果表明，增加TCR信号促进CD4+ T细胞的分层分化，逐步驱动克隆扩增、效应分化、记忆分化，并最终分化出能够稳定、长期持续的记忆群体。虽然先前的研究表明，TCR与抗原的高亲和性相互作用在选择CD4+效应T细胞应答者中起作用，但我们将尝试确定这些相互作用在选择CD4+记忆T细胞群以及刺激强大的二次应答中所起的作用。为了做到这一点，我们将对CD4+效应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亲和度CD4+记忆T细胞库中的作用。从广义上讲，我们将验证这样的假设，即随着抗原信号在初次反应中增加，CD4+ T细胞经历分层分化阶段，其中最强的信号导致CD4+记忆T细胞群稳定。

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.