Selective Instructions for Memory T Cells

描述（由申请方提供）：粘液效应记忆CD 8 T细胞（TEM）位于粘膜上皮，具有增强的即时效应功能。相比之下，记忆T细胞驻留在淋巴组织内，需要增殖和分化才能成为迁移到上皮表面的效应细胞。TEM在病原体进入部位的积累对于保护性免疫是必不可少的，但是驱动粘膜记忆细胞分化的机制知之甚少。我们的初步数据表明，由高亲和力/亲合力TCR信号诱导的活化诱导的CD 8aa可以选择性地将胸腺细胞和成熟的CD 8 T细胞从活化诱导的细胞死亡（AICD）中拯救出来，使它们成为记忆T细胞。此外，我们的数据还表明，高亲和力的CD 8aa配体，小鼠胸腺白血病（TL）抗原，诱导一些APC和肠上皮细胞组成型表达，可能作为第二个选择性的关键组成部分，以确保长期积累的最适合的效应细胞（CD 8aa+）形成粘膜TEM。目前的提案旨在为这些令人兴奋的、突破性的和非常重要的初步观测提供坚实的证据。 公共卫生相关性：艾滋病毒疫苗接种试验的持续失败是一个明确的警告，即迄今为止使用的疫苗接种方法不能在自然抗艾滋病毒的人中复制控制病毒的自然免疫力。它们还表明，迫切需要更好地理解和表征驱动自然记忆的机制和因素，并可用于直接有效的疫苗诱导的保护性免疫。因此，理解和鉴定可以指导疫苗诱导的分化和维持高效和长寿的免疫记忆的机制和因素是至关重要的。到目前为止，我们的研究表明，淋巴和粘膜记忆都是保护所必需的，但粘膜免疫的缺乏导致免疫防御显着受损，这可能是开发有效HIV疫苗的努力受挫的最重要原因之一。我们提出的研究旨在调查我们从以前的研究中获得的新方向和新见解，这可能会导致重要的新信息，这些信息对于设计新颖有效的策略来对抗毁灭性感染和癌症非常重要。

DESCRIPTION (provided by applicant): Mucosal effector memory CD8 T cells (TEM) are located at mucosal epithelium and have a heightened and immediate effector function. By contrast, memory T cells residing within lymphoid tissues and require proliferation and differentiation to become effector cells that migrate to epithelial surfaces. The accumulation of TEM at the pathogen entry site(s) is essential for protective immunity, but the mechanisms that drive the differentiation of mucosal memory cells are poorly understood. Our preliminary data indicate that activation-induced CD8aa, induced by high affinity/avidity TCR signals, might selectively rescue thymocytes and mature CD8 T cells from activation induced cell death (AICD) allowing them to become memory T cells. Furthermore, our data also suggest that the high-affinity CD8aa ligand, the mouse thymus leukemia (TL) antigen, induced on some APCs and constitutively expressed on intestinal epithelial cells, might serve as a second selective key component to assure the long-term accumulation of the fittest effector cells (CD8aa+) to form mucosal TEM. The current proposal is designed to provide solid evidence for these exciting, breakthrough and highly significant initial observations. PUBLIC HEALTH RELEVANCE: The continued failure of HIV vaccination trials is a clear warning that the vaccination approaches used so far do not reproduce natural immunity that controls the virus in natural HIV resistant people. They also signify a serious need for a better understanding and characterization of mechanisms and factors that drive natural memory and that could be applied to direct effective vaccine-induced protective immunity. It is therefore of utmost importance to understand and identify the mechanisms and factors that can direct vaccine-induced differentiation and maintenance of highly effective and long-lived immune memory. Our studies so far, suggest that both lymphoid and mucosal memory are required for protection, but that the absence of mucosal immunity leads to a significant impaired immune defense, which might be one of the most significant causes of setbacks in the fierce effort to develop an effective HIV vaccine. Our proposed study aims to investigate a new direction and new insights that we have gained from the previous research, that likely will lead to significant new information important for the design of novel and effective strategies to combat devastating infections and cancers.