title: Enhanced phosphoinositide 3-kinase δ activity is a frequent event in systemic lupus erythematosus that confers resistance to activation-induced T cell death.
abstract: Systemic lupus erythematosus (SLE) is a human chronic inflammatory disease caused by the action of autoreactive T and B cells. Class I phosphoinositide-3-kinases (PI3K) are enzymes that trigger formation of 3-poly-phosphoinositides that induce cell survival. Enhanced PI3K activation is a frequent event in human cancer. Nonetheless, in a genetic model with enhanced activation of class I(A) PI3K in T cells, mice show a greater tumor index but die of a lupus-like disease. In this study, we studied the potential PI3K involvement in human SLE. The PI3K pathway was frequently activated in SLE patient PBMC and T cells (∼70% of cases), more markedly in active disease phases. We examined the mechanism for PI3K pathway activation and found enhanced activation of PI3Kδ in SLE peripheral blood T cells. The magnitude of PI3K pathway activation in patients paralleled activated/memory T cell accumulation. We examined potential tolerance mechanisms affected by increased PI3K activity; SLE patients showed reduced activation-induced cell death of activated/memory T cells. Moreover, the defective activation-induced cell death in SLE T cells was corrected after reduction of PI3Kδ activity, suggesting that PI3Kδ contributes to induction of enhanced SLE memory T cell survival. These observations point to PI3Kδ as a target of clinical interest for SLE.
authors.affiliation: Department of Immunology and Oncology, National Center of Biotechnology/Spanish National Research Council, Madrid E-28049, Spain.
authors.forename: Abel
authors.initials: A
authors.lastname: Suárez-Fueyo
authors.forename: Domingo F
authors.initials: DF
authors.lastname: Barber
authors.forename: Jorge
authors.initials: J
authors.lastname: Martínez-Ara
authors.forename: Antonio C
authors.initials: AC
authors.lastname: Zea-Mendoza
authors.forename: Ana C
authors.initials: AC
authors.lastname: Carrera
mesh_terms: D064413:3-Phosphoinositide-Dependent Protein Kinases; D000328:Adult; D017209:Apoptosis / Q000276:immunology; D015153:Blotting, Western; D002469:Cell Separation; D002470:Cell Survival / Q000276:immunology; D004789:Enzyme Activation / Q000276:immunology; D005260:Female; D005434:Flow Cytometry; D019084:Fluorescent Antibody Technique, Indirect; D006801:Humans; D007156:Immunologic Memory; D008180:Lupus Erythematosus, Systemic / Q000201:enzymology* / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D019869:Phosphatidylinositol 3-Kinases / Q000276:immunology / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D055815:Young Adult
chemical_list: D064413:3-Phosphoinositide-Dependent Protein Kinases; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases