title: Functional human regulatory T cells fail to control autoimmune inflammation due to PKB/c-akt hyperactivation in effector cells.
abstract: During the last decade research has focused on the application of FOXP3(+) regulatory T cells (Tregs) in the treatment of autoimmune disease. However, thorough functional characterization of these cells in patients with chronic autoimmune disease, especially at the site of inflammation, is still missing. Here we studied Treg function in patients with juvenile idiopathic arthritis (JIA) and observed that Tregs from the peripheral blood as well as the inflamed joints are fully functional. Nevertheless, Treg-mediated suppression of cell proliferation and cytokine production by effector cells from the site of inflammation was severely impaired, because of resistance to suppression. This resistance to suppression was not caused by a memory phenotype of effector T cells or activation status of antigen presenting cells. Instead, activation of protein kinase B (PKB)/c-akt was enhanced in inflammatory effector cells, at least partially in response to TNFα and IL-6, and inhibition of this kinase restored responsiveness to suppression. We are the first to show that PKB/c-akt hyperactivation causes resistance of effector cells to suppression in human autoimmune disease. Furthermore, these findings suggest that for a Treg enhancing strategy to be successful in the treatment of autoimmune inflammation, resistance because of PKB/c-akt hyperactivation should be targeted as well.
authors.affiliation: Center for Molecular and Cellular Intervention, Department of Immunology, Wilhelmina Children’s Hospital, University Medical Center Utrecht, Utrecht, The Netherlands. ewehrens@umcutrecht.nl
authors.forename: Ellen J
authors.initials: EJ
authors.lastname: Wehrens
authors.forename: Gerdien
authors.initials: G
authors.lastname: Mijnheer
authors.forename: Chantal L
authors.initials: CL
authors.lastname: Duurland
authors.forename: Mark
authors.initials: M
authors.lastname: Klein
authors.forename: Jenny
authors.initials: J
authors.lastname: Meerding
authors.forename: Jorg
authors.initials: J
authors.lastname: van Loosdregt
authors.forename: Wilco
authors.initials: W
authors.lastname: de Jager
authors.forename: Birgit
authors.initials: B
authors.lastname: Sawitzki
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Coffer
authors.forename: Bas
authors.initials: B
authors.lastname: Vastert
authors.forename: Berent J
authors.initials: BJ
authors.lastname: Prakken
authors.forename: Femke
authors.initials: F
authors.lastname: van Wijk
mesh_terms: D000293:Adolescent; D001171:Arthritis, Juvenile / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D001327:Autoimmune Diseases / Q000276:immunology / Q000473:pathology / Q000628:therapy; D016175:B-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism*; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D004789:Enzyme Activation; D006801:Humans; D007165:Immunosuppression Therapy; D016219:Immunotherapy, Adoptive; D007249:Inflammation / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D008297:Male; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000502:physiology* / Q000637:transplantation; D017211:Treatment Failure; D015854:Up-Regulation
chemical_list: D051057:Proto-Oncogene Proteins c-akt