In contrast to conventional T cells that recognize peptides on MHC proteins, CD1 molecules present lipid antigens to T lymphocytes. The abundant expression of CD1a hallmarks Langerhans cells in the skin, a subtype of dendritic cell (DC) with antigen-presenting functions. CD1a can bind and display a broad spectrum of lipid antigens derived from exogenous sources, such as bacteria, or host origin. The intricate immune system of the skin is critically involved in responses to extrinsic insults like allergens, as well as in autoimmune diseases, such as psoriasis. However, the in vivo role of CD1a on Langerhans cells remains unclear, principally because CD1a is expressed in humans but lacking in mice. To overcome this obstacle, we generated human CD1a-transgenic mice and investigated the impact of CD1a on skin inflammation. Here we show that the lipidic molecule urushiol from the plant poison ivy induces severe skin inflammation in a CD1a-dependent fashion. The immune response is exclusively driven by CD1a-expressing Langerhans cells that elicit the generation of CD4 T cells, producing the inflammatory cytokines IL-17 and IL-22. Notably, human subjects with poison ivy dermatitis showed a similar cytokine signature following CD1a-mediated urushiol recognition. Among different urushiol congeners, we identified diunsaturated pentadecylcatechol (C15:2) as the dominant antigen for CD1a-restricted T cells. We determined the crystal structure of the CD1a-urushiol (C15:2) complex to 1.9Å resolution, demonstrating the molecular basis of urushiol interaction with the antigen-binding cleft of CD1a. In a model for psoriasis, CD1a massively amplified inflammation mediated by Th17 cells reactive with self lipid antigens from skin. Strikingly, treatment with blocking antibodies against CD1a fully abrogated skin inflammation. Patients suffering from psoriasis showed strong inflammatory T cell activation in response to CD1a. Thus, we propose CD1a as a novel target for future therapeutic strategies against inflammatory skin diseases.