Mallaun Michel, Zenke Gerhard, Palmer Ed
Laboratory of Transplantation Immunology and Nephrology, Department of Biomedicine, University Hospital Basel, Basel, Switzerland.
J Recept Signal Transduct Res. 2010 Dec;30(6):430-43. doi: 10.3109/10799893.2010.518151. Epub 2010 Oct 14.
Although ZAP-70 is required for T-cell development, it's unclear how this kinase controls both positive and negative selection.
Using OT-I pre-selection thymocytes and a panel of peptide major histocompatibility complex (pMHC) ligands of defined affinity, the recruitment, phosphorylation and activity of ZAP-70 was determined at the interface with antigen-presenting cells (APCs).
pMHC ligands promoting negative selection induce a discrete elevation of ZAP-70 recruitment, phosphorylation and enzymatic activity in the thymocyte:APCs interface.
The quantity of ZAP-70 kinase activity per cell is a key parameter controlling the fate of a developing thymocyte since partial inhibition of ZAP-70 kinase activity converted negative into positive selection. Surprisingly, the amount of ZAP-70 enzymatic activity observed during negative selection is not controlled by differential phosphorylation of the ZAP-70 protein but rather by the total amount of T-cell receptor and co-associated ZAP-70 recruited to the thymocyte:APC interface.
These data provide evidence that a burst of ZAP-70 activity initiates the signaling pathways for negative selection.
尽管ZAP - 70是T细胞发育所必需的，但尚不清楚这种激酶如何控制阳性和阴性选择。
使用OT - I预选胸腺细胞和一组具有确定亲和力的肽主要组织相容性复合体（pMHC）配体，在与抗原呈递细胞（APC）的界面处测定ZAP - 70的募集、磷酸化和活性。
促进阴性选择的pMHC配体在胸腺细胞与APC的界面处诱导ZAP - 70募集、磷酸化和酶活性的离散升高。
每个细胞中ZAP - 70激酶活性的量是控制发育中胸腺细胞命运的关键参数，因为对ZAP - 70激酶活性的部分抑制会将阴性选择转变为阳性选择。令人惊讶的是，在阴性选择期间观察到的ZAP - 70酶活性的量不是由ZAP - 70蛋白的差异磷酸化控制的，而是由募集到胸腺细胞与APC界面的T细胞受体和共相关ZAP - 70的总量控制的。
这些数据提供了证据，表明ZAP - 70活性的爆发启动了阴性选择的信号通路。
