Role of sub-activation-threshold TCR interactions in maintaining T cell memory

描述（由申请人提供）：在这个项目中，我们研究了在一次感染期间形成的免疫记忆是如何在面对多个不相关病原体的重复感染时免于消除的。这一点很重要，因为稳定的记忆对于成功地赋予终身保护性免疫至关重要。了解这一机制将使我们能够改进疫苗，否则需要频繁增强，甚至开发针对疟疾等疾病的新疫苗。尽管诸如il - 7和IL-15之类的细胞因子维持了免疫系统中记忆T细胞库的绝对大小，但确保群体包括所有先前经历的充分代表的途径尚不清楚。基于我们最近的工作，我们假设维持不同的CD4+记忆库需要记忆T细胞与内源性亚阈配体（STLs）的营养相互作用。stl是一种独特的肽- mhc复合物，它太弱而不能刺激传统的T细胞活化。由于只有一小部分记忆细胞参与特定的STL，因此生存竞争仅限于这些小的T细胞“菌落”。这种机制的意义在于，它避免了如果竞争更广泛可能发生的更大范围的曲目损失。我们已经产生了独特的试剂和开发的方法来测试这一创新的假设使用两个主要的独立和互补的目标。1. 利用最近发现的共享抗原特异性或stl特异性的tcr，确定tcr特异性如何决定哪些T细胞可以在记忆维持过程中竞争。我们将研究这种竞争的细胞机制，并确定它对T细胞多克隆库的影响范围。2. 利用疟原虫、流感和弓形虫的连续感染，评估对新感染的反应如何破坏预先存在的记忆T细胞的稳定性。我们还将探讨在这种情况下，STL治疗如何帮助恢复记忆T细胞的稳定性。在完成后，我们期望对CD4+记忆维持提供新的理解，并提出在过继治疗和疫苗接种期间提高记忆T细胞存活率的策略。相反的策略可以帮助降低自身免疫和移植过程中致病性T细胞的频率。

DESCRIPTION (provided by applicant): In this project we examine how immunological memory formed during one infection is protected from erasure in the face of repeated subsequent infections by multiple unrelated pathogens. This is significant because stable memory is essential for immunizations to successfully confer lifelong protective immunity. Understanding this mechanism will allow us to improve vaccines that otherwise require frequent boosting and even develop new ones for diseases such as malaria. Although cytokines such as IL7 and IL-15 maintain the absolute size of the memory T cell pool in the immune system, the pathways ensuring that the population includes adequate representation of all the previous experiences, is not known. Based on our recent work, we hypothesize that the maintenance of a diverse CD4+ memory repertoire requires trophic interactions of memory T cells with endogenous sub- threshold ligands (STLs). STLs are distinct peptide-MHC complexes that are too weak to stimulate conventional T cell activation. Since only a small proportion of memory cells engage a particular STL, competition for survival is limited to these small "colonies" of T cells. The significance of this mechanism is that it avoids a much broader repertoire loss that might happen if the competition was more widespread. We have generated unique reagents and developed methodologies to test this innovative hypothesis using two major independent and complimentary aims. 1. Establish how TCR-specificity determines which T cells can compete during memory maintenance, using recently identified TCRs that either share antigen-specificity or STL-specificity. We will examine the cellular mechanisms for such competition and establish the range of impact it has on a polyclonal repertoire of T cells. 2. Using sequential infections with Plasmodium, Influenza and Toxoplasma, evaluate how pre-existing memory T cells can be destabilized by the response to a new infection. We will also explore how STL- treatment can help restore the stability of memory T cells in this context. On completion, we expect to offer a novel understanding of CD4+ memory maintenance and suggest strategies to improve memory T cell survival during adoptive therapies and vaccinations. The converse strategies can help decrease the frequency of pathogenic T cells during autoimmunity and transplantation.