Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, Center for Molecular Immunology and Infectious Disease, University Park, Pennsylvania, United States of America.
PLoS One. 2010 Jan 26;5(1):e8891. doi: 10.1371/journal.pone.0008891.
T cell development is critically dependent on both the environment and signals delivered by the T cell Receptor (TCR). The Tec family kinase Itk has been suggested to be an amplifier of signals emanating from the TCR and the loss of Itk partially affects most stages of thymopoiesis. Loss of Itk also differentially affects the development of conventional vs. non-conventional or innate memory phenotype T cells. Here, we examine whether these lineage choices are affected by a combination of TCR affinity and Itk by analyzing mice lacking Itk and carrying two TCR transgenes with differing affinities, OT-II and DO11.10. Our results show that developing thymocytes receive a gradient of signals, DO11.10>OT-II>DO11.10/Itk(-/-)>OT-II/Itk(-/-). We also show that the development of CD4(+) T cells is controlled by TCR signaling via Itk, which regulates the expression of the transcription factor, Th-POK, an enforcement factor for CD4 commitment. This results in a reduction in CD4(+) T cell development, and an increase in the development of MHC class II restricted TCR transgenic CD8(+) T cells that resemble non-conventional or innate memory phenotype CD8 T cells. This alteration accompanies increased expression of Runx3 and its target genes Eomesodermin, Granzyme B and Perforin in Itk null OT-II CD4(+) thymocytes. All together, these data suggest that Itk plays an important role in CD4/CD8 commitment by regulating signal thresholds for the lineage commitment. Our data also suggest that the lower level of TCR signaling that occurs with a low affinity TCR in the absence of Itk can redirect some MHC class II restricted CD4(+) T cell to class II-restricted CD8(+) innate memory phenotype T cells.
T 细胞的发育严重依赖于环境和 T 细胞受体（TCR）传递的信号。Tec 家族激酶 Itk 被认为是 TCR 发出的信号的放大器，Itk 的缺失部分影响胸腺生成的大多数阶段。Itk 的缺失也会对常规和非常规或先天记忆表型 T 细胞的发育产生不同的影响。在这里，我们通过分析缺乏 Itk 并携带两种具有不同亲和力的 TCR 转基因的小鼠（OT-II 和 DO11.10）来研究这些谱系选择是否受 TCR 亲和力和 Itk 的组合影响。我们的结果表明，发育中的胸腺细胞接收到 DO11.10>OT-II>DO11.10/Itk(-/-)>OT-II/Itk(-/-)的信号梯度。我们还表明，通过 Itk 通过 TCR 信号来控制 CD4(+)T 细胞的发育，Itk 调节转录因子 Th-POK 的表达，Th-POK 是 CD4 承诺的执行因子。这导致 CD4(+)T 细胞发育减少，以及 MHC 类 II 受限 TCR 转基因 CD8(+)T 细胞的发育增加，这些细胞类似于非常规或先天记忆表型 CD8 T 细胞。这种改变伴随着 Itk 缺失的 OT-II CD4(+)胸腺细胞中 Runx3 及其靶基因 Eomesodermin、Granzyme B 和 Perforin 的表达增加。所有这些数据表明，Itk 通过调节谱系定向的信号阈值在 CD4/CD8 承诺中发挥重要作用。我们的数据还表明，在缺乏 Itk 的情况下，低亲和力 TCR 发生的较低 TCR 信号水平可以将一些 MHC 类 II 受限的 CD4(+)T 细胞重新定向到 MHC 类 II 受限的 CD8(+)先天记忆表型 T 细胞。
