Zanni M P, von Greyerz S, Schnyder B, Brander K A, Frutig K, Hari Y, Valitutti S, Pichler W J
Institute of Immunology and Allergology, Inselspital, Bern, Switzerland.
J Clin Invest. 1998 Oct 15;102(8):1591-8. doi: 10.1172/JCI3544.
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 alphabeta+ T cells via a nonconventional presentation pathway based on a labile binding of the drug to MHC-peptide complexes.
药物的T细胞识别可通过半抗原-载体模型来解释，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，其被T细胞识别的机制尚不清楚。我们从对磺胺甲恶唑、利多卡因（无反应性药物）和头孢曲松（本身具有反应性的β-内酰胺抗生素）特异的过敏个体中生成T细胞克隆，并通过药物特异性刺激比较这些克隆细胞内游离钙浓度（[Ca2+]i）的增加以及T细胞受体（TCR）下调的动力学。所有测试药物均在特异性CD4(+)和CD8(+) T细胞克隆上诱导了MHC限制的、剂量和抗原呈递细胞（APC）依赖性的TCR下调。化学无反应性药物引起[Ca2+]i立即且持续增加以及快速的TCR下调，但仅当这些药物以溶液形式添加到APC和克隆细胞中时才会出现这种情况。相比之下，以溶液形式添加化学有反应性的半抗原头孢曲松需要> 6小时才能诱导TCR下调。当APC与头孢曲松预孵育时，观察到TCR的快速下调和细胞因子分泌，这表明共价修饰肽的稳定呈递。我们的数据证明了药物呈递给活化的特异性T细胞的两种不同途径。本身具有反应性的头孢曲松在与载体肽共价结合后呈递。无反应性药物可通过基于药物与MHC-肽复合物不稳定结合的非常规呈递途径被特异性αβ+ T细胞识别。
