Control over the activation of the immune system is central to the key issues of human health. Autoimmunity, atopy, persistent infections and tumours all share a common root cause in a sub-optimal balance between immune activity and tolerance. At the heart of this balance are T cells, with the capacity for both activation and suppression. Research in mouse models has allowed enormous progress to be made on understanding fundamental mechanics, and yet the next step translating this understanding into therapeutics has proven far more difficult than originally anticipated. The basis of this problem may be a reliance on the mouse model without parallel human research. In this project we propose to create a dynamic interplay between the technological advantages of working in mouse models and the physiological relevance of studying the human immune system in three key research areas.The first research track is a gene discovery program, using an immunology-orientated approach to allow the discovery of important human disease genes that remain invisible to clinically-orientated approaches. The second research track is a functional genomics program, seeking to address the mechanistic questions that arise from traditional disease-gene association studies. This information is of critical importance in translating genetic data into therapeutic interventions and provides the basis for personalised medicine. The third research track is a direct hypothesis-driven project testing the role that genetic variation in the target organ alters susceptibility to autoimmune disease. Each of these research tracks utilises cutting edge technology in genetics and immunology, combining knowledge from mouse models with innovative study design in human populations.