Chemicals, such as metal ions in jewellery or hair dyes, are common causes of allergic contact dermatitis, an inflammatory skin disease with a notable socio-economic impact. The most important contact allergen is nickel, to which about 11% of the European population reacts positive in the diagnostic patch test. To prevent allergic reactions and protect public health, chemicals undergo regulatory tests, which, however, fail to predict the strong allergenic property of metal ions, pointing out knowledge gaps. This project contributed to an improved understanding of the misguided human immune reaction to nickel and other major contact allergens, which is orchestrated by a cell type called T cells. Our group established a novel in vitro method - the “activation-induced marker (AIM) assay” - that identifies chemical-reactive T cells in blood with unprecedented sensitivity. The AIM assay offers key advantages, including speed and comprehensiveness, detecting activated T cells after just 5 hours. Using the AIM assay, we showed that allergic individuals have a higher frequency of chemical-reactive T cells in their blood compared to non-allergic individuals, which indicates further potential as a blood-based in vitro diagnostic test. Still, non-allergic individuals displayed a strong basal immune reaction, which we quantified and explained by identifying the exact binding points of the metal allergens Ni2+, Co2+ and Pd2+ to the immune receptors on the T cells. Our findings elucidate, why so many T cells respond to metal ions even in individuals without metal allergy and likely why metal allergies are so prevalent in the population. We also have a better understanding of why current regulatory tests, which do not involve T cells, fail to capture the high sensitizing potency of metal ions. Complementary investigations revealed a very low skin penetration capacity of e. g., palladium ions, which may explain, combined with regulatory effects, why strongly T cell reactive metal ions may not induce skin allergy even more often. We extended the application of the AIM assay to a hair dye. In addition, we elucidated cross-reactivities, which underly cross-allergies where an allergic individual reacts to a second allergen because the same immune receptors are triggered. Cross-reactivity is a property of high interest in basic immunology research and currently insufficiently described. Finally, we also tracked the relevant immune receptors in the inflamed skin of patients, which helps to prove their in vivo relevance and to identify culprit allergens at the site of inflammation. Overall, a better basic mechanistic understanding of the immune cells involved in allergic reaction to chemicals has been achieved, serving future solutions for unmet diagnostic and regulatory needs. As a next step, an expansion of the AIM assay to additional chemicals and areas such as lung sensitization or drug hypersensitivity is warranted.