HLA-restricted, processing- and metabolism-independent pathway of drug recognition by human αβ T lymphocytes
HLA-restricted, processing- and metabolism-independent pathway of drug recognition by human αβ T lymphocytes
复制标题
DOI：
10.1172/jci3544
复制
发表时间：
1998-10-15
影响因子：
15.9
通讯作者：
Pichler, WJ
中科院分区：
文献类型：
--
作者：
Zanni, MP;von Greyerz, S;Pichler, WJ
T细胞对药物的识别是由半抗原载体模型解释的，这意味着化学反应性药物与载体蛋白的共价结合。然而，大多数药物是无反应性的，它们对T细胞的识别是不清楚的。我们从对磺胺甲恶唑、利多卡因（非反应性药物）和头孢三松（本身就是反应性β -内酰胺抗生素）具有特异性的过敏个体中生成了T细胞克隆，并比较了细胞内游离钙浓度（[Ca2+](i)）的增加和药物特异性刺激下这些克隆的T细胞受体（TCR）下调的动力学。所有测试的药物诱导mhc限制性，剂量和抗原呈递细胞（APC）依赖性TCR下调特异性CD4（+）和CD8(+) T细胞克隆。化学非反应性药物引起立即和持续的[Ca2+](i)增加和快速的TCR下调，但只有当这些药物加入到APC和克隆的溶液中时。相比之下，在溶液中加入化学反应性半抗原头孢曲松（ceftriaxone）则需要60 h才能诱导TCR下调。当APC与头孢曲松预孵育时，观察到TCR和细胞因子分泌的快速下调，表明共价修饰肽的稳定呈现。我们的数据显示了两种不同的药物呈递到活化的特异性T细胞的途径。本身反应性头孢曲松是在与载体肽共价结合后呈现的。非反应性药物可以通过基于药物与mhc肽复合物不稳定结合的非常规呈递途径被特异性α - β (+) T细胞识别。
T cell recognition of drugs is explained by the hapten-carrier model, implying covalent binding of chemically reactive drugs to carrier proteins. However, most drugs are nonreactive and their recognition by T cells is unclear. We generated T cell clones from allergic individuals specific to sulfamethoxazole, lidocaine (nonreactive drugs), and cef-triaxone (per se reactive beta-lactam antibiotic) and compared the increase of intracellular free calcium concentration ([Ca2+](i)) and the kinetics of T cell receptor (TCR) downregulation of these clones by drug-specific stimulations. All drugs tested induced an MHC-restricted, dose- and antigen-presenting cell (APC)-dependent TCR downregulation on specific CD4(+) and CD8(+) T cell clones. Chemically nonreactive drugs elicited an immediate and sustained [Ca2+](i) increase and a rapid TCR downregulation, but only when these drugs were added in solution to APC and clone. In contrast, the chemically reactive hapten ceftriaxone added in solution needed > 6 h to induce TCR downregulation. When APC were preincubated with ceftriaxone, a rapid downregulation of the TCR and cytokine secretion was observed, suggesting a stable presentation of a covalently modified peptide. Our data demonstrate two distinct pathways of drug presentation to activated specific T cells. The per se reactive ceftriaxone is presented after covalent binding to carrier peptides. Nonreactive drugs can be recognized by specific alpha beta(+) T cells via a nonconventional presentation pathway based on a labile binding of the drug to MHC-peptide complexes.