Grant: Operating Grant

Our immune system is supposed to fight off dangerous pathogens such as viruses but save our body's own cells. Also, it should tolerate harmless environmental antigens such as pollens. Many diseases are caused not only by failing immunity against pathogens but also by immune cells erroneously attacking body's own cells (autoimmunity) or over-reacting to innocuous antigens (allergy). A group of white blood cells, termed T cells, play central roles in guiding the immune system to keep the fine balance between immunity and tolerance. To do so, T cells utilize two types of cell surface sensors, namely, T cell antigen receptor (TCR) and T cell costimulators. Using TCR, T cells distinguish whether the antigen is self or non-self; through the costimulators, T cells can tell the level of danger the antigen conveys. Upon antigenic challenges, T cells integrate the "signals" generated by TCR and costimulators and mount full immune responses to only those that are both "non-self" and "dangerous". Obviously, manipulation of T cell costimulators has proven to be an effective way to potentiate the immunity (e.g., during vaccination) or suppress undesirable immune reactions such as autoimmune diseases, allergy, inflammation, and graft rejection. The "inducible costimulator (ICOS)" is one of the most potent T cell costimulators in multiple aspects of T cell immunity. Using genetically modified mouse models we generated, our research group is elucidating how ICOS works at the molecular and cellular level. Based on the knowledge we gain from our studies, we test the role of ICOS and its signaling components in mouse models of human diseases: parasite infection, rheumatoid arthritis, and complications in bone marrow transplantation (graft vs. host disease). Our research aims to link basic T cell biology to improvement of human health.