Final Report Summary - MOLMECHSNKTOX (Molecular Mechanisms of Natural Killer cell Cytotoxicity) Patients with immunodeficiencies impairing lymphocyte cytotoxicity typically manifest with life-threatening sepsis-like conditions triggered by infection, with viruses in particular, and caused by excessive proliferation of activated immune cells. Treatment includes chemo-immunotherapy and, in the case of familial disease, subsequent hematopoietic stem cell transplantation, after which the survival rate in children has gone up to around 65% in recent years. To date, only a limited number of genes have been identified as causative of such immunodeficiencies, and a majority of clinical cases remain unexplained, creating difficulties for diagnosis. It is therefore critical to expand our understanding of these syndromes and the role of cytotoxic T cells and natural killer (NK) cells in the disease course. A more complete knowledge of these molecular mechanisms may provide opportunities for new therapies, and a full map of the proteins that regulate cytotoxicity will enable further genetic screening in patients with unexplained immunodeficiencies. This project concerns investigations into the molecular mechanisms of cytotoxic lymphocyte function in the context of human immunodeficiencies, in particular the elucidation of presynaptic signaling cascades involving protein families that regulate vesicle trafficking and membrane fusion required for NK cell exocytosis and function. A cross-disciplinary approach was employed for this study, utilizing cutting-edge skills and knowledge in cell biology, immunology and proteomics, as well as insight from other medical fields.During the course of this study, we have understood that the signaling pathways involving effector proteins regulating NK cell exocytosis are indeed quite complex, and therefore further time is required for more conclusive results to be finalized. Hence, several daughter projects stem out of the original protocol, and are ongoing as a result of this program, with very promising preliminary results.The knowledge obtained through this study, and related ongoing work, significantly contributes to the understanding of the complex molecular mechanisms involved in NK cell lytic granule exocytosis, and thus facilitates the diagnosis and treatment of patients suffering from various, as yet uncured, immunodeficiency syndromes. Moreover, advances in this area offer economic benefits to the public and the private sector alike, and the benefits positively impact the whole European Community.
