Selective Instructions for Memory T Cells

描述(申请人提供)：粘膜效应记忆CD8 T细胞位于粘膜上皮细胞，具有增强的即刻效应功能。相比之下，位于淋巴组织内的记忆T细胞需要增殖和分化才能成为迁移到上皮表面的效应细胞。在病原体进入部位(S)积累的透射电子显微镜对于保护性免疫是必不可少的，但驱动粘膜记忆细胞分化的机制尚不清楚。我们的初步数据表明，由高亲和力/亲和力TCR信号诱导的激活诱导的CD8aa可能选择性地将胸腺细胞和成熟的CD8T细胞从激活诱导的细胞死亡(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CD8aa配体，即小鼠胸腺白血病(TL)抗原，在一些APC上诱导并在肠上皮细胞上结构性表达，可能是确保最适合的效应细胞(CD8aa+)长期积累以形成粘膜透射电子显微镜的第二个选择性关键成分。目前的提议旨在为这些令人兴奋的、突破性的和非常重要的初步观察提供坚实的证据。 与公共卫生相关：艾滋病毒疫苗接种试验继续失败是一个明确的警告，即迄今使用的疫苗接种方法不能在对艾滋病毒具有天然抵抗力的人身上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描述驱动自然记忆的机制和因素，并将其应用于指导有效的疫苗诱导的保护性免疫。因此，了解和确定能够指导疫苗诱导分化和维持高效和长期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了免疫防御的显著受损，这可能是开发有效的HIV疫苗的激烈努力受挫的最重要原因之一。我们拟议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的有效策略来对抗毁灭性的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.