Cytokine signaling in developing thymocytes and T cells

关于T细胞发育的传统观点认为，来自相同T细胞受体（TCR）的信号决定阳性和阴性选择以及成熟CD 4+辅助细胞和CD 8+细胞毒性细胞的谱系选择。如何实现这一点的确切机制仍存在争议，但有人提出，TCR信号传导中的定量或定性差异将解释谱系选择的不同结果。与这些观点相反，在这里，我们表明，TCR信号本身是不足以确定细胞的命运发展胸腺细胞，和CD 4/CD 8谱系的选择需要额外的线索，如白细胞介素-7（IL-7）的细胞因子。使用IL-7受体的直接下游信号分子的条件性缺失，我们证明了IL-7诱导的细胞因子信号是CD 8谱系选择和体内分化为成熟CD 8+细胞毒性T细胞所需的。我们的数据建立了一个以前不受重视的作用，在体内IL-7和其他γ c-细胞因子的CD 8谱系承诺的未成熟胸腺细胞，这是一致的动力学信号模型的T细胞谱系的选择。

The conventional view on T cell development posits that signals from the same T cell receptor (TCR) determines both positive and negative selection as well as lineage choice into mature CD4+ helper and CD8+ cytotoxic cells. The precise mechanism how this is achieved is still under dispute but it has been proposed that either quantitative or qualitative differences in TCR signaling would account for the different outcomes of lineage choice. In contrast to such views, here we show that TCR signaling alone is not sufficient to determine cell fate of developing thymocytes, and that CD4/CD8 lineage choice requires additional cues by cytokines such as interleukin-7 (IL-7). Using conditional deletion of immediate downstream signaling molecules of the IL-7 receptor, we demonstrate that IL-7 induced cytokine signals are required for CD8 lineage choice and for the differentiation into mature CD8+ cytotoxic T cells in vivo. Our data establish a previously unappreciated role for in vivo IL-7 and other gamma c-cytokines in CD8 lineage commitment of immature thymocytes, which is consistent with the kinetic signaling model of T cell lineage choice.