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

描述（由申请人提供）：在本项目中，我们研究了在一次感染过程中形成的免疫记忆如何在多次不相关病原体的重复后续感染中免受擦除。这一点很重要，因为稳定的记忆对于成功赋予终身保护性免疫力的免疫接种至关重要。了解这一机制将使我们能够改进疫苗，否则需要频繁加强，甚至开发新的疾病，如疟疾。 虽然细胞因子如IL-7和IL-15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性的途径尚不清楚。基于我们最近的工作，我们假设维持多样化的CD 4+记忆库需要记忆T细胞与内源性亚阈值配体（STL）的营养相互作用。STL是不同的肽-MHC复合物，其太弱而不能刺激常规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“集落”。这一机制的重要性在于，它避免了在竞争更广泛的情况下可能发生的更广泛的保留曲目损失。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.使用最近鉴定的具有抗原特异性或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期间竞争。我们将研究这种竞争的细胞机制，并建立它对T细胞多克隆库的影响范围。2.使用疟原虫，流感和弓形虫的连续感染，评估预先存在的记忆T细胞如何通过对新感染的反应而不稳定。我们还将探讨STL治疗如何在这种情况下帮助恢复记忆T细胞的稳定性。完成后，我们希望提供一个新的理解CD 4+记忆维持，并提出策略，以提高记忆T细胞的生存在过继治疗和疫苗接种。匡威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.