Cytokine signals play an essential role in lymphocyte function and development. Disregulation of these signals can impede T cell development and lead to autoimmunity. The complex, multi-chain structure of many cytokine receptors has made it hard to examine the role of specific cytokines and receptors in human disease. This project examines the role of the common gamma chain (Gc) and its signals in lymphoid development and function. Gamma chain deficient mice were generated by homologous recombination and their lymphoid system was examined. These mice exhibited a range of interesting immunologic abnormalities. Interestingly, despite the lack of Gc signals, T cell accumulate in these animals. Our current findings indicate that this accumulation is due to a failure in normal mechanisms of lymphocyte homeostasis and tolerance. The development of this animal model should provide and important vehicle for testing therapies s for the treatment of autoimmune disease and immune deficiencies such as XSCID. This group reviews products for the treatment of autoimmunity and for hematologic reconstitution following intensive chemotherapy. Cytokine signals clearly play a role in both these processes and many current therapies for these condition involve treatment with cytokines. However, because of the complexity of cytokine receptor systems, the role played by specific cytokines and their signals has been difficult to evaluate. Specificlly, because cytokine receptor chains are often shared between several different cytokine receptors, treatment with a particular cytokine may have unexpected toxicities. The development and characterization of mice with this specific defect in the common gamma chain will be helpful in developing and testing products for the treatment of autoimmune disease and evaluating potential cytokine induced toxicities. Most importantly, these common gamma chain deficient mice provide an important model of the human immunodeficiency syndrome and can provide a direct a powerful preclinical model of gene therapy for human XSCID.