T cell survival

NAVE CD8 T细胞通过与自身多肽和MHC复合体相互作用，既需要IL-7信号又需要TCR信号，以维持T细胞的动态平衡。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信号不够，因为IL-7信号本身可以提供强大的生存信号。由于IL-7信号可以下调IL-7R的表达，我们假设IL-7R的下调对初治CD8 T细胞的稳态和生存造成了问题。为了解决这个问题，我们使用了在人CD2启动子的控制下表达IL-7R的转基因T细胞，而CD2启动子不受IL-7刺激的下调。我们发现IL-7R、TG、NAVE、CD8 T细胞在IL-7的刺激下，在体外能显著增殖。提示IL-7ra表达的维持对IL-7的增殖具有重要作用。HY TCR TG女性T细胞不能进行动态平衡增殖，因为它们与自身配体的TCR亲和力太低。我们发现它们的IL-7R的表达非常低，并且可以被更强的TCR信号上调。有趣的是，将IL-7Ra TG引入HY T细胞可以挽救它们的稳态增殖。因此，我们发现了一种新的T细胞稳态机制，在这种机制中，稳态TCR信号介导了IL-7R表达的维持。

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.