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

Details

Serval ID
serval:BIB_7518
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
HLA-restricted, processing- and metabolism-independent pathway of drug recognition by human alpha beta T lymphocytes.
Journal
Journal of Clinical Investigation
Author(s)
Zanni M.P., von Greyerz S., Schnyder B., Brander K.A., Frutig K., Hari Y., Valitutti S., Pichler W.J.
ISSN
0021-9738 (Print)
ISSN-L
0021-9738
Publication state
Published
Issued date
1998
Volume
102
Number
8
Pages
1591-1598
Language
english
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
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.
Keywords
Antigen Presentation, Antigen-Presenting Cells/immunology, Calcium Signaling, Ceftriaxone/immunology, Dose-Response Relationship, Drug, Down-Regulation, HLA Antigens/immunology, Haptens/immunology, Humans, Lidocaine/immunology, Mepivacaine/immunology, Models, Immunological, Receptors, Antigen, T-Cell, alpha-beta, Sulfamethoxazole/immunology, Superantigens/immunology, T-Lymphocytes/immunology
Pubmed
Web of science
Open Access
Yes
Create date
19/11/2007 13:45
Last modification date
20/08/2019 15:32
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