T cell survival

T细胞存活

• 批准号: 7733505
• 负责人: Alfred Singer
• 金额: $ 25.34万
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7733505
• 关键词: Address; Affinity; Antigens; CD8B1 gene; Cell Survival; Cells; Cytokine Receptors; Down-Regulation; Female; Genes; Goals; Homeostasis; Human; In Vitro; Interleukin-7; Ligands; Maintenance; Malignant Neoplasms; Mediating; Peptide/MHC Complex; Physiological; Proliferating; Receptor Signaling; Signal Transduction; T-Lymphocyte; Transgenic Organisms; promoter; response

Nave CD8 T cells require both IL-7 signaling and TCR signaling through the interaction with self peptides and MHC complex for T cell homeostasis. However nobody knows why these cells require two signals or why IL-7 signaling is not enough, since IL-7 signaling by itself can provide strong survival signals. Because IL-7 signaling can down-regulate IL-7R expression, we hypothesizes that down-regulation of IL-7R causes a problem for nave CD8 T cell homeostasis and survival. To address this question, we used T cells expressing transgenic IL-7R under the control of the human CD2 promoter which is not down-regulated by IL-7 stimulation. We found that IL-7R Tg nave CD8 T cells can proliferate dramatically in vitro in response to IL-7. This suggests that the maintenance of IL-7Ra expression is important for the proliferation by IL-7. HY TCR Tg female T cells cannot undergo homeostatic proliferation because their TCR affinity to self ligand is too low. We found that their IL-7R expression is very low and can be up-regulated by stronger TCR signaling. Interestingly, introducing an IL-7Ra Tg to HY T cells rescued their homeostatic proliferation. Consequently, we have discovered a new mechanism of T cell homeostasis in which homeostatic TCR signaling mediates the maintenance of IL-7R expression.

原始 CD8 T 细胞需要 IL-7 信号传导和 TCR 信号传导，通过与自身肽和 MHC 复合物相互作用来实现 T 细胞稳态。然而，没有人知道为什么这些细胞需要两个信号，或者为什么 IL-7 信号传导不够，因为 IL-7 信号传导本身可以提供强烈的生存信号。由于 IL-7 信号传导可以下调 IL-7Rα 表达，因此我们假设 IL-7R 的下调会导致幼稚 CD8 T 细胞稳态和存活出现问题。为了解决这个问题，我们使用了在人 CD2 启动子控制下表达转基因 IL-7R 的 T 细胞，该启动子不会因 IL-7 刺激而下调。我们发现IL-7R Tg nave CD8 T细胞可以在体外响应IL-7而急剧增殖。这表明IL-7Ra表达的维持对于IL-7的增殖很重要。 HY TCR Tg 雌性 T 细胞不能进行稳态增殖，因为它们的 TCR 与自身配体的亲和力太低。我们发现它们的 IL-7R 表达非常低，并且可以通过更强的 TCR 信号传导上调。 有趣的是，将 IL-7Ra Tg 引入 HY T 细胞可以挽救其稳态增殖。 因此，我们发现了 T 细胞稳态的新机制，其中稳态 TCR 信号介导 IL-7R 表达的维持。