Immunological health relies on a balance between the ability to mount an immune response against potential pathogens and tolerance to self. However, how we keep that balance in health and what goes wrong in disease is not well understood. Here, I will describe combination of novel experimental and computational approaches using multi-omics datasets, imaging and functional experiments to dissect the role and defects in immune cells across several disease areas in cancer and autoimmunity. We show how shared mechanisms that are disrupted across diseases, including cellular, migration, immuno-surveillance, regulation and activation, as well as the immunological features associated with better prognosis and immunomodulation.