Maturation of established antiviral CD8 T cell memory

通过接种疫苗或病原体暴露所赋予的对传染病的增强保护依赖于特异性免疫记忆的产生和保存。大多数抗病毒和许多抗菌免疫应答的基本组成部分是病原体特异性CD8+T细胞免疫的产生。 在急性疾病消退后，特异性CD8+效应T细胞经历一个过程，该过程将确定的效应T细胞亚群的选择与其逐渐成熟相结合，并最终建立特异性CD8+T细胞记忆。特异性CD8+T细胞记忆的保存对于减少继发性感染、最小化临床疾病和避免受感染宿主的潜在死亡的能力是不可或缺的。然而，在维持病原体特异性CD8 T细胞记忆的机制仍然不完全清楚。许多因素，如持续存在的抗原，交叉反应的病原体，非特异性炎症改变和年龄相关的过程可以不断重塑建立 CD8+T细胞记忆和免疫宿主的潜在损害保护。 在我们最近对长期抗病毒CD8+T细胞记忆的研究中，我们发现从效应T细胞到记忆T细胞的转变所需的时间比以前认识的要长得多。尽管在初次感染后约6周建立的抗病毒CD8+T细胞记忆表现出成熟T细胞记忆的特征，但我们观察到一个持续约1年的延长的表型和功能成熟过程。令人惊讶的是，老年CD8+ 记忆T细胞似乎准备提供比年轻的CD8+记忆T细胞更好的保护。 本研究计划旨在系统地确定已建立的抗病毒CD8+T细胞记忆逐渐成熟的分子基础，并验证衰老可能在一定程度上改善次级T细胞免疫的假设。我们希望这些研究将提供有关病原体特异性CD8+T细胞记忆的性质，范围和生理限制的重要线索。具有确定的表型和功能特征的老化的CD8+TM可以提供增强的保护的概念将为我们的T细胞记忆的概念化以及在临床相关病症（例如感染性疾病、肿瘤性疾病、自身免疫性疾病）下的预防性和治疗性干预提供重要基础。 和移植。

Heightened protection from infectious disease as conferred by vaccination or pathogen exposure relies on the generation and preservation of specific immunological memory. An essential component of most antiviral and many antibacterial immune responses is the generation of pathogen-specific CD8+T cell immunity. Following resolution of acute disease, specific CD8+ effector T cells are subject to a process that combines the selection of defined effector T cell subsets with their gradual maturation and culminates in the establishment of specific CD8+T cell memory. The preservation of specific CD8+T cell memory is integral to the capacity to curtail secondary infections, minimize clinical disease and avert potential death of infected hosts. However, the mechanisms operative in the maintenance of pathogen-specific CD8T cell memory remain incompletely understood. Numerous factors such as persisting antigen, cross-reactive pathogens, non-specific inflammatory alterations and age-associated processes can continuously remodel established CD8+T cell memory and potentially compromise protection of the immunized host. In our recent work on long-term, antiviral CD8+T cell memory, we have found that the transition from effector to memory T cells takes far longer than previously appreciated. Although antiviral CD8+T cell memory established approximately 6 weeks after initial infection exhibits the hallmarks of mature T cell memory, we observed an extended phenotypic and functional maturation process that lasts up to approximately1 year. Surprisingly, aged CD8+ memory T cells appear poised to provide better protection than young CD8+ memory T cells. This research proposal is designed to systematically define the molecular basis of the progressive maturation of established antiviral CD8+T cell memory and to test the hypothesis that aging may, to a certain extent, improve secondary T cell immunity. We expect that these studies will provide essential clues about the nature, scope and physiological limitations of pathogen-specific CD8+T cell memory. The notion that aged CD8+TM with defined phenotypic and functional features can provide enhanced protection will provide an important basis for our conceptualization of T cell memory as well as for prophylactic and therapeutic interventions under clinically relevant conditions such as infectious diseases, neoplastic disease, utoimmunity and transplantation.