T cell survival

T细胞存活

• 批准号: 8763351
• 负责人: Alfred Singer
• 金额: $ 24.47万
• 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/8763351
• 关键词: Address; Affinity; Antigens; CD8B1 gene; Cell Survival; Cell physiology; 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.

Nave CD 8 T细胞通过与自身肽和MHC复合物的相互作用需要IL-7信号传导和TCR信号传导以用于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信号是不够的，因为IL-7信号本身可以提供强大的生存信号。由于IL-7信号转导可以下调IL-7 R的表达，我们假设IL-7 R的下调导致幼稚CD 8 T细胞稳态和存活的问题。为了解决这个问题，我们使用了在人CD 2启动子控制下表达转基因IL-7 R的T细胞，该启动子不受IL-7刺激的下调。我们发现IL-7 R Tg nave CD 8 T细胞可以在体外响应IL-7而显著增殖。这表明IL-7 Ra表达的维持对于IL-7的增殖是重要的。HY TCR Tg雌性T细胞不能经历稳态增殖，因为它们的TCR对自身配体的亲和力太低。我们发现它们的IL-7 R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-7 Ra Tg引入HY T细胞拯救了它们的稳态增殖。因此，我们发现了一种新的T细胞稳态机制，其中稳态TCR信号传导介导IL-7 R表达的维持。