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Class I_B-Phosphatidylinositol 3-Kinase (PI3K) Deficiency Ameliorates I_A-PI3K-Induced Systemic Lupus but Not T Cell Invasion¹

Domingo F. Barber^*, Almira Bartolomé^*, Carmen Hernandez^*, Juana M. Flores, Cristina Fernandez-Arias^*, Luis Rodríguez-Borlado^*, Emilio Hirsch, Matthias Wymann, Dimitrios Balomenos^* and Ana C. Carrera^2,*

^* Department of Immunology and Oncology, and Animal Facility, Centro Nacional de Biotecnología/Consejo Superior de Investigaciones Cientificas, Universidad Autónoma de Madrid, Cantoblanco, Madrid, Spain; Department of Animal Medicine and Surgery, Veterinary School, Universidad Complutense de Madrid, Madrid, Spain; Department of Genetics Biology and Biochemistry, University of Torino, Turin, Italy; and Institute of Biochemistry, University of Fribourg, Fribourg, Switzerland

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 (PI3K), 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-PI3K 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 isoform thus decreased survival of pathogenic CD4⁺ memory cells, selectively inhibiting systemic lupus development. These results validate the PI3K isoform as a target for systemic lupus erythematosus treatment.

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