Interaction of sulfonamide derivatives with the TCR of sulfamethoxazole-specific human alpha beta(+) T cell clones

Drugs like sulfamethoxazole (SMX) or lidocaine can be presented to specific human alpha beta(+) T cell clones (TCC) by undergoing a noncovalent associ ation with MHC-peptide complexes on HLA-matched APCs, For a better understa nding of the molecular basis of the recognition of such drugs by specific T CC, we investigated 1) the fine specificity of the recognizing TCR, 2) the dose-response relationship for the induction of proliferation or cytokine p roduction, and 3) the mechanism of TCR triggering. For that purpose, we tes ted the reactivity of 11 SMX-specific CD4(+) TCC and 2 SMX-specific CD8(+) TCC to a panel of 13 different sulfonamide derivatives bearing the same cor e structure. Five of 13 clones recognized only SMX, while all other clones were responding to as many as 6 different compounds. Some of the compounds needed up to two orders of magnitude higher concentrations than SMX to stim ulate TCC, thereby displaying features of weak agonists, Different clones s howed clear differences in the minimal drug concentration required for the induction of a proliferative response. Therefore, weaker or stronger agonis tic properties were not a characteristic of a given sulfonamide derivative but rather an intrinsic property of the reacting TCR, Finally, the number o f down-regulated TCRs was a logarithmic function of the ligand concentratio n, implicating that specific T cells were activated by serial TCR engagemen t. Our data demonstrate that, despite the special way of presentation, nonp eptide Ag like drugs appear to interact with the TCR of specific T cells in a similar way as peptide Ags.