O'Shea J J, McVicar D W, Kuhns D B, Ortaldo J R
Leukocyte Cell Biology Section, Program Resources, Inc./DynCorp, National Cancer Institute, Frederick, MD 21702-1201.
J Immunol. 1992 Apr 15;148(8):2497-502.
NK cells, CD3- large granular lymphocytes, have diverse means by which they lyse targets, including antibody-dependent cellular cytotoxicity. The low affinity receptor for the Fc portion of Ig (Fc gamma RIIIA), like the TCR, is a multimeric receptor complex coupled to a protein tyrosine kinase. In the present study, we observed that inhibition of tyrosine kinase activity by herbimycin A interferes with receptor-mediated phosphorylation of a variety of substrates and mobilization of intracellular calcium. Fc gamma RIIIA induced IL-2R alpha-chain expression was also extremely sensitive to herbimycin A as was antibody-dependent cellular cytotoxicity, in fact more so than receptor-mediated phosphorylation and calcium mobilization. In contrast to Fc gamma RIIIA, the surface molecules and biochemical mechanisms involved in NK cytotoxicity and lymphokine-activated killing are not well characterized. Interestingly, however, herbimycin A also blocks these modes of cytolysis, implicating a role for tyrosine kinase function in these processes. Whether FcR-mediated signaling and receptor-mediated signaling involved in NK activity share specific biochemical intermediates is not known, but the involvement of tyrosine kinase function in the latter means of cytotoxicity may provide novel avenues for understanding the biochemical basis of this perplexing cellular function.
自然杀伤（NK）细胞，即CD3阴性大颗粒淋巴细胞，具有多种裂解靶标的方式，包括抗体依赖性细胞毒性。免疫球蛋白（Ig）Fc段的低亲和力受体（FcγRIIIA）与T细胞受体（TCR）一样，是一种与蛋白酪氨酸激酶偶联的多聚体受体复合物。在本研究中，我们观察到，除草霉素A对酪氨酸激酶活性的抑制会干扰受体介导的多种底物的磷酸化以及细胞内钙的动员。FcγRIIIA诱导的白细胞介素-2受体α链表达对除草霉素A也极为敏感，抗体依赖性细胞毒性同样如此，实际上比受体介导的磷酸化和钙动员更敏感。与FcγRIIIA不同，NK细胞毒性和淋巴因子激活杀伤所涉及的表面分子和生化机制尚未得到充分表征。然而，有趣的是，除草霉素A也会阻断这些细胞溶解方式，这表明酪氨酸激酶功能在这些过程中发挥作用。Fc受体介导的信号传导与NK活性中涉及的受体介导的信号传导是否共享特定的生化中间体尚不清楚，但酪氨酸激酶功能参与后者的细胞毒性作用可能为理解这种复杂细胞功能的生化基础提供新的途径。
