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无关病原体的重复后续感染时被擦除的。这一点意义重大，因为稳定的记忆是免疫成功授予终身保护性免疫的关键。了解这一机制将使我们能够改进原本需要频繁加强的疫苗，甚至为疟疾等疾病开发新的疫苗。尽管IL-7和IL-15等细胞因子维持免疫系统中记忆T细胞池的绝对大小，但确保人群包括所有先前经验的充分代表的途径尚不清楚。根据我们最近的工作，我们假设维持一个多样化的CD4+记忆谱系需要记忆T细胞与内源性亚阈值配体(STL)的营养相互作用。STL是一种独特的多肽-MHC复合体，太弱，不能刺激传统的T细胞激活。由于只有一小部分记忆细胞参与了特定的STL，因此生存的竞争仅限于这些小的T细胞“群体”。这一机制的意义在于，它避免了更广泛的曲目损失，如果竞争更广泛，可能会发生这种情况。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假设，使用两个主要的独立和互补的目标。1.使用最近发现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细胞在记忆维持期间可以竞争。我们将研究这种竞争的细胞机制，并确定它对T细胞多克隆谱系的影响范围。2.使用疟疾、流感和弓形虫的连续感染，评估对新感染的反应如何破坏原有的记忆T细胞的稳定性。我们还将探索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CD4+记忆维持，并建议策略，以提高记忆T细胞在过继治疗和疫苗接种期间的存活率。相反的策略可以帮助降低自身免疫和移植过程中致病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.