HLA-restricted, processing- and metabolism-independent pathway of drug recognition by human αβ T lymphocytes

被引:186
作者
Zanni, MP
von Greyerz, S
Schnyder, B
Brander, KA
Frutig, K
Hari, Y
Valitutti, S
Pichler, WJ [1 ]
机构
[1] Inselspital Bern, Inst Immunol & Allergol, CH-3010 Bern, Switzerland
[2] Univ Lausanne, Inst Biochem, CH-1066 Epalinges, Switzerland
关键词
drug hypersensitivity; T cell receptor downregulation; alpha beta(+) T lymphocytes; nonpeptide T cell antigens; drug presentation;
D O I
10.1172/JCI3544
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
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.
引用
收藏
页码:1591 / 1598
页数:8
相关论文
共 31 条
[1]   RECOGNITION OF A LIPID ANTIGEN BY CD1-RESTRICTED ALPHA-BETA(+) T-CELLS [J].
BEEKMAN, EM ;
PORCELLI, SA ;
MORITA, CT ;
BEHAR, SM ;
FURLONG, ST ;
BRENNER, MB .
NATURE, 1994, 372 (6507) :691-694
[2]  
BRANDER C, 1995, J IMMUNOL, V155, P2670
[3]   HUMAN V-GAMMA-9-V-DELTA-2 CELLS ARE STIMULATED IN A CROSS-REACTIVE FASHION BY A VARIETY OF PHOSPHORYLATED METABOLITES [J].
BURK, MR ;
MORI, L ;
DELIBERO, G .
EUROPEAN JOURNAL OF IMMUNOLOGY, 1995, 25 (07) :2052-2058
[4]   PEPTIDE BINDING AND PRESENTATION BY MOUSE CD1 [J].
CASTANO, AR ;
TANGRI, S ;
MILLER, JEW ;
HOLCOMBE, HR ;
JACKSON, MR ;
HUSE, WD ;
KRONENBERG, M ;
PETERSON, PA .
SCIENCE, 1995, 269 (5221) :223-226
[5]   Major histocompatibility complex-independent recognition of a distinctive pollen antigen, most likely a carbohydrate, by human CD8(+) alpha/beta T cells [J].
Corinti, S ;
DePalma, R ;
Fontana, A ;
Gagliardi, MC ;
Pini, C ;
Sallusto, F .
JOURNAL OF EXPERIMENTAL MEDICINE, 1997, 186 (06) :899-908
[6]   SULFAMETHOXAZOLE IS METABOLIZED TO THE HYDROXYLAMINE IN HUMANS [J].
CRIBB, AE ;
SPIELBERG, SP .
CLINICAL PHARMACOLOGY & THERAPEUTICS, 1992, 51 (05) :522-526
[7]   CALCIUM AND LYMPHOCYTE-T ACTIVATION [J].
GARDNER, P .
CELL, 1989, 59 (01) :15-20
[8]   LYMPHOCYTE-ACTIVATION IN CUTANEOUS DRUG-REACTIONS [J].
HERTL, M ;
MERK, HF .
JOURNAL OF INVESTIGATIVE DERMATOLOGY, 1995, 105 (01) :S95-S98
[9]   TRANSFORMATION OF LUPUS-INDUCING DRUGS TO CYTOTOXIC PRODUCTS BY ACTIVATED NEUTROPHILS [J].
JIANG, XX ;
KHURSIGARA, G ;
RUBIN, RL .
SCIENCE, 1994, 266 (5186) :810-813
[10]   CD1 presentation of microbial nonpeptide antigens to T cells [J].
Jullien, D ;
Stenger, S ;
Ernst, WA ;
Modlin, RL .
JOURNAL OF CLINICAL INVESTIGATION, 1997, 99 (09) :2071-2074