Class I PI3K catalyzes formation of 3-poly-phosphoinositides. The family is divided into I A isoforms, activated by Tyr kinases and the I B isoform (PI3Kγ), activated by G protein-coupled receptors. Mutations that affect PI3K are implicated in chronic inflammation, although the differential contribution of each isoform to pathology has not been elucidated. Enhanced activation of class I A-PI3K in T cells extends CD4+ memory cell survival, triggering an invasive lymphoproliferative disorder and systemic lupus. As both I A-and I B-PI3K isoforms regulate T cell activation, and activated pathogenic CD4+ memory cells are involved in triggering systemic lupus, we examined whether deletion of I B could reduce the pathological consequences of increased I A-PI3K activity. I B-PI3Kγ deficiency did not abolish invasion or lymphoproliferation, but reduced CD4+ memory cell survival, autoantibody production, glomerulonephritis, and systemic lupus. Deletion of the I B-PI3Kγ isoform thus decreased survival of pathogenic CD4+ memory cells, selectively inhibiting systemic lupus development. These results validate the PI3Kγ isoform as a target for systemic lupus erythematosus treatment.