title: HLA-restricted, processing- and metabolism-independent pathway of drug recognition by human alpha beta T lymphocytes.
abstract: 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.
authors.affiliation: Institute of Immunology and Allergology, Inselspital, Bern, Switzerland.
authors.forename: M P
authors.initials: MP
authors.lastname: Zanni
authors.forename: S
authors.initials: S
authors.lastname: von Greyerz
authors.forename: B
authors.initials: B
authors.lastname: Schnyder
authors.forename: K A
authors.initials: KA
authors.lastname: Brander
authors.forename: K
authors.initials: K
authors.lastname: Frutig
authors.forename: Y
authors.initials: Y
authors.lastname: Hari
authors.forename: S
authors.initials: S
authors.lastname: Valitutti
authors.forename: W J
authors.initials: WJ
authors.lastname: Pichler
mesh_terms: D017951:Antigen Presentation; D000938:Antigen-Presenting Cells / Q000276:immunology; D020013:Calcium Signaling; D002443:Ceftriaxone / Q000276:immunology; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D006680:HLA Antigens / Q000276:immunology*; D006241:Haptens / Q000276:immunology; D006801:Humans; D008012:Lidocaine / Q000276:immunology; D008619:Mepivacaine / Q000276:immunology; D018448:Models, Immunological; D016693:Receptors, Antigen, T-Cell, alpha-beta; D013420:Sulfamethoxazole / Q000276:immunology*; D018089:Superantigens / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D006680:HLA Antigens; D006241:Haptens; D016693:Receptors, Antigen, T-Cell, alpha-beta; D018089:Superantigens; D002443:Ceftriaxone; D008012:Lidocaine; D008619:Mepivacaine; D013420:Sulfamethoxazole