Drugs can evoke T cell mediated hypersensitivity reactions, and have long been thought to do so by acting as haptens. While the molecular details of these interactions as well as the exact nature of the ensuing T cell activation have largely remained unknown, evidence has been accumulating that several if not many allergenic drugs activate T cells by interacting in a reversible, non-covalent way with the pertinent immune receptors, namely the major histocompatibility complex (MHC) proteins and / or the T cell receptor (TCR). Evidence presented in this proposal indicates that drugs interact with TCR transfectants reversibly and that the mode of interaction may differ depending on the drug class. Sulfanilamides seem to interact directly with the TCR since they partially or fully activate TCR transfectants in the absence of antigen-presenting cells (APC). Sulfanilamides also activate TCR that are specific for other small antigens like quinolones or nickel ions, indicating that they may be broadly cross-reactive with many TCR. Quinolones, on the other hand, are dependent on APC “help” for partial or full TCR activation and do not show a similar crossreactivity. Drug-induced activation of selected combinations of drugs and drug-specific TCR transfectants will be investigated in detail, in particular intracellular signaling cascades and the intracellular and plasma membrane relocation of signaling components. Methods include phosflow analysis and fluorescence microscopy. Key findings obtained with TCR transfectants will be replicated in primary T lymphocytes, T cell lines, and T cell clones of allergic or normal donors. Drug binding to TCR and MHC molecules will be assessed using BiaCore technology.This proposal presents evidence that drugs employ different mechanisms of non-covalent TCR activation and aims at a better understanding of these interactions and the resulting T cell activation. Ultimately, it would lead or at least contribute to a shift of paradigm in that chemical reactivity alone is not a defining hallmark for potential allergenicity of a drug. Further, the finding that low molecular weight molecules can activate T cells without the “help” of APC has implications for immunology in general as well, since it indicates that the control mechanisms of innate immunity, which are normally a prerequisite for the induction of an adaptive immune response, can be circumvented under special circumstances. Lastly, the presented results and proposed studies hold promise that TCR activation might be amenable to pharmacological regulation in analogy to the action of many low molecular weight compounds on a plethora of other cellular receptors and enzymes.