Presenilins regulate T cell development by modulating TCR signaling
Presenilins regulate T cell development by modulating TCR signaling
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2007
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通讯作者：
K. Laky;B. Fowlkes
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作者：
K. Laky;B. Fowlkes
第204卷，第9期，2007年9月3日2115-2129 www.jem.org/cgi/doi/ 2115 10.1084/jem.20070550在识别胸腺基质上的MHC配体后，TCR CD 4 CD 8（双阳性[DP]）胸腺细胞中的信号传导介导阳性选择和CD 4和CD 8的发育 T细胞。TCR信号的强度/持续时间决定DP胸腺细胞的命运的定量模型得到了广泛的支持。因此，最强的TCR信号通过缺失诱导负选择;中等TCR信号促进正选择和成熟至单阳性（SP）、CD 4 CD 8或CD 4 CD 8阶段;并且弱的或没有TCR信号导致细胞死亡。TCR信号的数量也被认为是CD 4和CD 8谱系定型的主要决定因素。在接受阳性选择范围内的TCR信号的DP胸腺细胞中，接受较强/延长信号的那些偏向于CD 4命运，而经历较弱/瞬时信号的那些接受CD 8命运（1-3）。该领域一个挑衅性且挥之不去的话题是DP胸腺细胞中数量不同的TCR信号如何在细胞内翻译以指定这些T细胞的命运。Notch信号通路是胸腺细胞中细胞命运的另一个重要调节因子。Notch对于淋巴前体向T细胞谱系的定型是必不可少的。Notch信号传导在双阴性（DN）CD 4 CD 8胸腺细胞中是通过DN 1-DN 4阶段成熟所必需的，在DN 1-DN 4阶段，Notch信号传导与诸如TCR重排、前TCR信号传导和免疫应答等关键功能相关。 / T谱系承诺（4-12）。Notch还涉及随后在DP胸腺细胞中启动的CD 4与CD 8谱系决定（13 - 15）。总的来说，这些数据表明，在整个胸腺细胞发育过程中可能需要反复/连续的Notch信号传导。尽管如此，一些实验方法已经产生了关于Notch信号传导在晚期阶段的作用的相互矛盾的结果。 T细胞发育。在缺乏单个Notch家族成员的小鼠中，SP胸腺细胞的发育是正常的（16 - 19）。还报道了通过转录调节因子CBF 1/Su（H）/Lag-1（CSL;也称为RBPJ）的条件性缺失或转录共激活因子Mastermind（dnMAML）的dn形式的表达来抑制Notch信号传导对CD 4/CD 8 T细胞命运没有影响（7，20）。同样，Notch拮抗剂Numb的过表达对发育没有明显影响（21）。与这些阴性结果相反，其他研究表明Notch确实在CD 4和CD 8 T细胞发育中发挥作用。当向胎儿胸腺器官培养物中加入药理学抑制剂以阻断Notch活化时，两项独立研究的作者得出结论，Notch活性促进CD 8。bfowlkes@nih.gov
Vol. 204, No. 9, September 3, 2007 2115-2129 www.jem.org/cgi/doi/ 2115 10.1084/jem.20070550 Upon recognition of MHC ligands on thymic stroma, TCR signaling in CD4 CD8 (double-positive [DP]) thymocytes mediates positive selection and the development of CD4 and CD8 T cells. There is broad support for quantitative models in which the strength/ duration of TCR signals determines the fate of a DP thymocyte. Accordingly, the strongest TCR signals induce negative selection by deletion; intermediate TCR signals promote positive selection and maturation to the single-positive (SP), CD4 CD8 or CD4 CD8 , stage; and weak or no TCR signals result in cell death. The quantity of the TCR signal has also been proposed to be a primary determinant in CD4 and CD8 lineage commitment. Among DP thymocytes receiving TCR signals within the range for positive selection, those receiving stronger/prolonged signals are biased toward the CD4 fate, whereas those experiencing weaker/ transient signals adopt the CD8 fate ( 1-3 ). A provocative and lingering topic in this fi eld is how quantitatively diff erent TCR signals in DP thymocytes are translated intracellularly to specify these T cell fates. The Notch signaling pathway is another important regulator of cell fate in thymocytes. Notch is essential for commitment of lymphoid precursors to the T cell lineage. Notch signaling is required in double-negative (DN) CD4 CD8 thymocytes for maturation through the DN1 – DN4 stages, where it has been associated with such critical functions as TCR rearrangement, pre-TCR signaling, and / T lineage commitment ( 4-12 ). Notch has also been implicated in the subsequent CD4 versus CD8 lineage decision that is initiated in DP thymocytes ( 13 – 15 ). Collectively, these data suggest that recurrent/ continuous Notch signaling may be required throughout thymocyte development. Nevertheless, several experimental approaches have yielded confl icting results on the role of Notch signaling in the late stages of T cell development. Development of SP thymocytes is normal in mice defi cient for individual Notch family members ( 16 – 19 ). Inhibiting Notch signaling either by conditional deletion of the transcriptional regulator CBF1/Su(H)/Lag-1 (CSL; also called RBPJ ) or expression of a dn form of the transcriptional coactivator Mastermind (dnMAML), were also reported to have no effect on CD4/CD8 T cell fate ( 7, 20 ). Likewise, overexpression of Numb, which is an antagonist of Notch, has no obvious eff ect on development ( 21 ). In contrast to these negative results, other studies imply that Notch does play a role in CD4 and CD8 T cell development. When pharmacological inhibitors were added to fetal thymic organ cultures to block Notch activation, the authors of two independent studies concluded that Notch activity promotes CD8 CORRESPONDENCE B.J. Fowlkes: bfowlkes@nih.gov