Activation of the Hedgehog signaling pathway in T-lineage cells inhibits TCR repertoire selection in the thymus and peripheral T-cell activation
Activation of the Hedgehog signaling pathway in T-lineage cells inhibits TCR repertoire selection in the thymus and peripheral T-cell activation
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T 谱系细胞中 Hedgehog 信号通路的激活抑制胸腺中 TCR 库的选择和外周 T 细胞的激活
作者：
N. Rowbotham;A. L. Hager;M. Cebecauer;D. Shah;E. Drakopoulou;J. Dyson;S. Outram;T. Crompton
在T细胞谱系中，TCR信号强度参与了许多细胞命运的决定。在这里，我们证明了Hedgehog(HH)信号诱导的转录事件降低了小鼠的TCR信号强度。通过表达转基因转录激活形式的Gli2(Gli2TCR2)在体内激活胸腺细胞中的HH信号，改变了胸腺细胞发育的许多阶段Δ连接的结果，使自身反应性细胞逃避克隆删除；减少了转基因TCR介导的阳性选择；降低了CD4CD8单阳性(SP)细胞的比例；减少了细胞表面CD5的表达。相反，Shh−/−胸腺中CD_4/CD_8细胞比例和对转基因T细胞受体的阳性和阴性选择均增加，表明Shh确实影响了T细胞受体的选择和生理状态下双阳性(DP)细胞向SP细胞的转变。在外周T细胞中，Gli2ERKn2的表达通过Δ磷酸化的上游机制减弱了T细胞的激活和增殖。
TCR signal strength is involved in many cell fate decisions in the T-cell lineage. Here, we show that transcriptional events induced by Hedgehog (Hh) signaling reduced TCR signal strength in mice. Activation of Hh signaling in thymocytes in vivo by expression of a transgenic transcriptional-activator form of Gli2 (Gli2ΔN2) changed the outcome of TCR ligation at many stages of thymocyte development, allowing self-reactive cells to escape clonal deletion; reducing transgenic TCR-mediated positive selection; reducing the ratio of CD4/CD8 single-positive (SP) cells; and reducing cell surface CD5 expression. In contrast, in the Shh−/− thymus the ratio of CD4/CD8 cells and both positive and negative selection of a transgenic TCR were increased, demonstrating that Shh does indeed influence TCR repertoire selection and the transition from double-positive (DP) to SP cell in a physiological situation. In peripheral T cells, Gli2ΔN2 expression attenuated T-cell activation and proliferation, by a mechanism upstream of ERK phosphorylation.
影响因子：
4.6
作者：
M. Matise;D. Epstein;Heidi L. Park;K. Platt;A. Joyner
通讯作者：
M. Matise;D. Epstein;Heidi L. Park;K. Platt;A. Joyner
影响因子：
6.5
作者：
Bull, JJ;Müller-Röver, S;Philpott, MP
通讯作者：
Philpott, MP