Grant: Foundation Grant

Self/nonself discrimination by T lymphocytes is a fundamental requirement of life in vertebrates and is implicated in most fatal diseases in humans. Indeed, i) nonself recognition is essential for elimination of microbes and cancer cells, while ii) immune responses against self antigens cause classic autoimmune diseases (e.g., type 1 diabetes, rheumatoid arthritis, multiple sclerosis) and are instrumental in chronic inflammatory diseases, hypertension and atherosclerosis. T lymphocytes learn how to distinguish self from nonself in the thymus. Importantly, the thymus ages more rapidly than all other organs, and by the age of 45 y, 75% of the thymus is lost in humans. Thymus senescence decreases the ability to recognize new antigens and responsiveness to vaccines, and increases the risk of infection, cancer and autoimmune diseases in ageing people. Hence, it is a sobering thought that our understanding of the molecular composition of the immune self is very rudimentary and that we do not understand the mechanisms of thymic involution. Accordingly, the two main themes of my research program are thymus biology and the molecular definition of the immune self. My specific objectives are i) to discover the molecular composition of the immune self, ii) to uncover how the immune self is perturbed in cancer cells, iii) to understand the rules governing T lymphocyte education in the thymus, and iv) to find a strategy to rejuvenate the thymus. Answers to these questions will be instrumental in i) treating thymus atrophy, the most common cause of immune deficiency in humans, ii) understanding the molecular bases of self-tolerance and enabling molecular evidence-based treatment of autoimmune and inflammatory conditions, and iii) discovering cancer-specific antigens that can be used as personalized vaccines for cancer treatment.