Drug interaction with T-cell receptors: T-cell receptor density determines degree of cross-reactivity

Background: Immune-mediated adverse reactions to drugs are often due to T-cell reactivity, and cross-reactivity is an important problem in pharmacotherapy. Objective: We investigated whether chemical inert drugs can stimulate T cells through their T-cell receptor (TCR) and analyzed the cross-reactivities to related compounds. Methods: We transfected human TCRs isolated from two drug-reactive T-cell clones (TCCs) by PCR into a TCR-negative mouse T-cell hybridoma. The TCCs were isolated from a patient with drug hypersensitivity to the antibacterial sulfonamide sulfamethoxazole (SMX). Results: The transfectants reacted to SMX only in the presence of antigen-presenting cells (APCs). Glutaraldehyde-fixed APCs, however, were sufficient to elicit T-cell stimulation, indicating a processing-independent direct interaction of the drug with the TCR and MHC molecule. The transfected hybridomas secreted IL-2 in a drug dose-dependent manner, whereas the degree of reactivity was dependent on the level of TCR expression. One transfectant reacted not only to SMX but also to related sulfonamide compounds. Interestingly, high TCR expression increased cross-reactivity to other structurally related compounds. In addition, SMX-specific TCR cross-reacted only with sulfonamides bearing a sulfanilamide core structure but not with sulfonamides such as celecoxib, furosemide, or glibenclamide. Conclusions: These results demonstrate that the T-cell reactivity to drugs is solely determined by the TCR. Moreover, these results show that cross-reactivity of structurally similar compounds correlates with the density of the TCR. Stably transfected T-cell hybridomas may represent a powerful screening tool for cross-reactivity of newly generated sulfonamide-containing compounds such as celecoxib