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

J Clin Invest. 1998 Oct 15;102(8):1591-8. doi: 10.1172/JCI3544.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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*


  • HLA Antigens
  • Haptens
  • Receptors, Antigen, T-Cell, alpha-beta
  • Superantigens
  • Ceftriaxone
  • Lidocaine
  • Mepivacaine
  • Sulfamethoxazole