Superantigen-induced T Cell:B cell conjugation is mediated by LFA-1 and requires signaling through Lck, but not ZAP-70
Superantigen-induced T Cell:B cell conjugation is mediated by LFA-1 and requires signaling through Lck, but not ZAP-70
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DOI：
10.4049/jimmunol.167.10.5708
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发表时间：
2001-11-15
影响因子：
4.4
通讯作者：
Burkhardt, JK
中科院分区：
文献类型：
--
作者：
Morgan, MM;Labno, CM;Burkhardt, JK
T细胞和APC之间结合的形成需要T细胞表面整合素的激活和细胞-细胞接触部位细胞骨架元件的内向信号重塑。这个信号通路中的早期事件还不是很清楚，可能不同于与固定化配体黏附的事件。我们发现Jurkat T细胞和呈递超抗原的EBV-B细胞之间的偶联形成是由LFA-1介导的，绝对需要LCK。Lek激酶、Src同源2或3结构域或肉豆蔻化位点的突变都会抑制与背景水平的结合，而Fyn的表达不能恢复粘附性。然而，ZAP-70缺失的细胞正常结合，表明Lek是LFA-1依赖的黏附所必需的，通过其他下游途径。几种抑制T细胞与固定在塑料上的ICAM-1黏附的药物，包括丝裂原激活蛋白/细胞外信号相关激酶、磷脂酰肌醇-3激酶和钙蛋白酶的抑制剂，不抑制结合。磷脂酶C和蛋白激酶C的抑制剂阻断野生型和ZAP-70缺陷细胞的结合，表明参与了不依赖ZAP-70激活的磷脂酶C。这些结果并不局限于Jurkat T细胞；抗原特异的初级T细胞母细胞的行为类似。虽然Lek信号增强LFA-1依赖的黏附的途径尚不清楚，但Nye发现缺乏功能Lek的细胞不能将F-肌动蛋白和LFA-1招募到T细胞：APC接触部位，而ZAP-70缺失的细胞表现出较温和的表型，其特征是接触部位的肌动蛋白和LFA-1排列紊乱。
The formation of a conjugate between a T cell and an APC requires the activation of integrins on the T cell surface and remodeling of cytoskeletal elements at the cell-cell contact site via inside-out signaling. The early events in this signaling pathway are not well understood, and may differ from the events involved in adhesion to immobilized ligands. We find that conjugate formation between Jurkat T cells and EBV-B cells presenting superantigen is mediated by LFA-1 and absolutely requires Lck. Mutations in the Lek kinase, Src homology 2 or 3 domains, or the myristoylation site all inhibit conjugation to background levels, and adhesion cannot be restored by the expression of Fyn. However, ZAP-70-deficient cells conjugate normally, indicating that Lek is required for LFA-1-dependent adhesion via other downstream pathways. Several drugs that inhibit T cell adhesion to ICAM-1 immobilized on plastic, including inhibitors of mitogen-activated protein/extracellular signal-related kinase kinase, phosphatidylinositol-3 kinase, and calpain, do not inhibit conjugation. Inhibitors of phospholipase C and protein kinase C block conjugation of both wild-type and ZAP-70-deficient cells, suggesting that a phospholipase C that does not depend on ZAP-70 for its activation is involved. These results are not restricted to Jurkat T cells; Ag-specific primary T cell blasts behave similarly. Although the way in which Lek signals to enhance LFA-1-dependent adhesion is not clear, Nye find that cells lacking functional Lek fail to recruit F-actin and LFA-1 to the T cell:APC contact site, whereas ZAP-70-deficient cells show a milder phenotype characterized by disorganized actin and LFA-1 at the contact site.