Class I-B-phosphatidylinositol 3-kinase (PI3K) deficiency ameliorates I-A-PI3K-induced systemic lupus but not T cell invasion

Class I PI3K catalyzes formation of 3-poly-phosphoinositides. The family is divided into I-A isoforms, activated by Tyr kinases and I-A the I-B isoform (PI3K gamma), 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 1(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-PI3K gamma deficiency did not abolish invasion or lymphoproliferation, but reduced CD4(+) memory cell survival, autoantibody production, glomerulonephritis, and systemic lupus. Deletion of the I-B-PI3K gamma isoform thus decreased survival of pathogenic CD4(+) memory cells, selectively inhibiting systemic lupus development. These results validate the PI3K gamma isoform as a target for systemic lupus erythernatosus treatment.