Class IB-phosphatidylinositol 3-kinase (PI3K) deficiency ameliorates IA-PI3K-induced systemic lupus but not T cell invasion.
Class I PI3K catalyzes formation of 3-poly-phosphoinositides. The family is divided into IA isoforms, activated by Tyr kinases and the IB isoform (PI3Kgamma), 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 IA-PI3K in T cells extends CD4+ memory cell survival, triggering an invasive lymphoproliferative disorder and systemic lupus. As both IA- and IB-PI3K isoforms regulate T cell activation, and activated pathogenic CD4+ memory cells are involved in triggering systemic lupus, we examined whether deletion of IB could reduce the pathological consequences of increased IA-PI3K activity. IB-PI3Kgamma deficiency did not abolish invasion or lymphoproliferation, but reduced CD4+ memory cell survival, autoantibody production, glomerulonephritis, and systemic lupus. Deletion of the IB-PI3Kgamma isoform thus decreased survival of pathogenic CD4+ memory cells, selectively inhibiting systemic lupus development. These results validate the PI3Kgamma isoform as a target for systemic lupus erythematosus treatment.
Barber
Domingo F
DF
Department of Immunology and Oncology, and Animal Facility, Centro Nacional de Biotecnología/Consejo Superior de Investigaciones Cientificas, Universidad Autónoma de Madrid, Cantoblanco, Madrid, Spain.
Bartolomé
Almira
A
Hernandez
Carmen
C
Flores
Juana M
JM
Fernandez-Arias
Cristina
C
Rodríguez-Borlado
Luis
L
Hirsch
Emilio
E
Wymann
Matthias
M
Balomenos
Dimitrios
D
Carrera
Ana C
AC
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000201:enzymology* / Q000276:immunology; D004195:Disease Models, Animal; D005434:Flow Cytometry; D007527:Isoenzymes / Q000172:deficiency / Q000276:immunology; D007674:Kidney Diseases / Q000209:etiology / Q000276:immunology / Q000473:pathology; D008180:Lupus Erythematosus, Systemic / Q000150:complications / Q000276:immunology*; D051379:Mice; D008822:Mice, Transgenic; D019869:Phosphatidylinositol 3-Kinases / Q000172:deficiency* / Q000276:immunology*
D007527:Isoenzymes; D019869:Phosphatidylinositol 3-Kinases