The role of CD45 in the immune system has been studied for many years. Our lab has proposed a model for CD45 regulation in which CD45 activity is inhibited by homodimerization. This inhibition is mediated by a structure called the "wedge," and mutation of the wedge prevents inhibition, resulting in background dependent autoimmunity. To study the contribution of the CD45 wedge mutation to autoimmunity on the C57BL/6 background, we crossed the wedge mutation to two other autoimmune prone strains of mice on this background, the complement C4 knockout and the Fas mutation lpr. While combination of C4 deficiency with the wedge mutation did not alter the phenotype of mice compared to single mutant controls, the wedge and lpr mutations cooperated, significantly enhancing lymphoproliferation and autoantibody production. The lymphoproliferation consisted of both activated T and B cells. Restricting T cells to the ovalbumin peptide specific OT2 TCR transgene eliminated T cell activation and reduced lymphoproliferation, suggesting that signaling through the TCR was leading to T cell activation. Furthermore, both T and B cells were necessary for lymphoproliferation, as genetic deletion of either cell type also prevented lymphoproliferation. However, B cell activation remained increased even in the absence of T cells, suggesting that wedge/lpr mutant B cells are intrinsically activated and may be responsible for initiating the process of lymphoproliferation by activating T cells.