Lymphocyte homeostasis requires the coordinate regulation of signaling cascades governing proliferation, differentiation, and death. Dysregulation of these processes is a necessary prerequisite for the development of lymphoid malignancies. Our lab recently reported a novel murine model containing a mutation that disrupts the negative regulation of the receptor-like protein tyrosine phosphatase CD45 during dimerization. These mice develop a profound lymphoproliferative disorder with polyclonal activation of T and B cells, massive splenomegaly, and premature death. A subset also develops stigmata of autoimmunity including anti-double stranded DNA antibody formation and immune complex-mediated glomerulonephritis. To define the cell type responsible for disease generation, the CD45 mutant mice were mated to mice deficient in T, B, or T and B cells. Genetic elimination of B cells, but not T cells results in ablation of the autoimmune and lymphoproliferative disorders. In contrast, absence of T cells resulted in a dramatic increase in the prevalence of lymphoma. These observations support the hypothesis that precise regulation of CD45 function by dimerization is essential for the maintenance of homeostasis within the hematopoietic system. Disruption of this function can have profound consequences leading to lymphoproliferation, autoimmunity, and malignancy. The goal of this proposal is to define the molecular and cellular basis for the breakdown of homeostasis and to identify the steps required for the development of lymphomas. The first aim tests B cell-intrinsic mechanisms that contribute to disease initiation. The second aim focuses on contributions from the microenvironment that may enhance B cell expansion and the mechanisms by which T cells inhibit lymphomagenesis. In the third aim, biochemical and gene expression analyses are used to address the molecular basis by which the CD45 mutation contributes to disease. Array CGH and ENU mutagenesis are used to begin to identify cooperating events that contribute to the progression from hyperproliferating to malignant state. These studies should provide important insights into the links between immune regulation, autoimmunity, and lymphoid malignancies as well as improve our understanding of the mechanisms governing immune surveillance.