Selective Instructions for Memory T Cells

描述（由申请人提供）：粘膜效应记忆CD8 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中，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保护性免疫至关重要，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/亲和度TCR信号诱导的活化诱导CD8aa可能选择性地拯救胸腺细胞和成熟cd8t细胞免于活化诱导细胞死亡（AICD），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组成性表达，可能是第二个选择性的关键成分，以确保最合适的效应细胞（CD8aa+）长期积累形成粘膜TEM。目前的建议旨在为这些令人兴奋的、突破性的和高度重要的初步观察提供确凿的证据。

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.