HLA-RESTRICTED, PROCESSING-INDEPENDENT AND METABOLISM-INDEPENDENT PATHWAY OF DRUG RECOGNITION BY HUMAN ALPHA-BETA T-LYMPHOCYTES

T cell recognition of drugs is explained by the hapten-carrier model, implying covalent binding of chemically reactive drugs to carrier prot eins. However, most drugs are nonreactive and their recognition by T c ells is unclear. We generated T cell clones from allergic individuals specific to sulfamethoxazole, lidocaine (nonreactive drugs), and cef-t riaxone (per se reactive beta-lactam antibiotic) and compared the incr ease of intracellular free calcium concentration ([Ca2+](i)) and the k inetics of T cell receptor (TCR) downregulation of these clones by dru g-specific stimulations. All drugs tested induced an MHC-restricted, d ose- and antigen-presenting cell (APC)-dependent TCR downregulation on specific CD4(+) and CD8(+) T cell clones. Chemically nonreactive drug s elicited an immediate and sustained [Ca2+](i) increase and a rapid T CR downregulation, but only when these drugs were added in solution to APC and clone. In contrast, the chemically reactive hapten ceftriaxon e added in solution needed > 6 h to induce TCR downregulation. When AP C were preincubated with ceftriaxone, a rapid downregulation of the TC R and cytokine secretion was observed, suggesting a stable presentatio n of a covalently modified peptide. Our data demonstrate two distinct pathways of drug presentation to activated specific T cells. The per s e 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.