HLA-restricted, Processing- and Metabolism-independent Pathway of Drug Recognition by Human ab T Lymphocytes

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 b -lactam antibiotic) and compared the increase of intracellular free calcium concentration ([Ca 2 1 ] i ) and the kinetics of T cell receptor (TCR) downregulation of these clones by drug-specific stimulations. All drugs tested induced an MHC-restricted, doseand antigen-presenting cell (APC)-dependent TCR downregulation on specific CD4 1 and CD8 1 T cell clones. Chemically nonreactive drugs elicited an immediate and sustained [Ca 2 1 ] 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 ab 1 T cells via a nonconventional presentation pathway based on a labile binding of the drug to MHC–peptide complexes. ( J. Clin. Invest. 1998. 102:1591–1598.)