title: Accumulation of peripheral autoreactive B cells in the absence of functional human regulatory T cells.
abstract: Regulatory T cells (Tregs) play an essential role in preventing autoimmunity. Mutations in the forkhead box protein 3 (FOXP3) gene, which encodes a transcription factor critical for Treg function, result in a severe autoimmune disorder and the production of various autoantibodies in mice and in IPEX (immune dysregulation, polyendocrinopathy, enteropathy, X-linked) patients. However, it is unknown whether Tregs normally suppress autoreactive B cells. To investigate a role for Tregs in maintaining human B-cell tolerance, we tested the reactivity of recombinant antibodies isolated from single B cells isolated from IPEX patients. Characteristics and reactivity of antibodies expressed by new emigrant/transitional B cells from IPEX patients were similar to those from healthy donors, demonstrating that defective Treg function does not impact central B-cell tolerance. In contrast, mature naive B cells from IPEX patients often expressed autoreactive antibodies, suggesting an important role for Tregs in maintaining peripheral B-cell tolerance. T cells displayed an activated phenotype in IPEX patients, including their Treg-like cells, and showed up-regulation of CD40L, PD-1, and inducibl T-cell costimulator (ICOS), which may favor the accumulation of autoreactive mature naive B cells in these patients. Hence, our data demonstrate an essential role for Tregs in the establishment and the maintenance of peripheral B-cell tolerance in humans.
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06511, USA.
authors.forename: Tuure
authors.initials: T
authors.lastname: Kinnunen
authors.forename: Nicolas
authors.initials: N
authors.lastname: Chamberlain
authors.forename: Henner
authors.initials: H
authors.lastname: Morbach
authors.forename: Jinyoung
authors.initials: J
authors.lastname: Choi
authors.forename: Sangtaek
authors.initials: S
authors.lastname: Kim
authors.forename: Joseph
authors.initials: J
authors.lastname: Craft
authors.forename: Lloyd
authors.initials: L
authors.lastname: Mayer
authors.forename: Caterina
authors.initials: C
authors.lastname: Cancrini
authors.forename: Laura
authors.initials: L
authors.lastname: Passerini
authors.forename: Rosa
authors.initials: R
authors.lastname: Bacchetta
authors.forename: Hans D
authors.initials: HD
authors.lastname: Ochs
authors.forename: Troy R
authors.initials: TR
authors.lastname: Torgerson
authors.forename: Eric
authors.initials: E
authors.lastname: Meffre
mesh_terms: D001327:Autoimmune Diseases / Q000276:immunology / Q000473:pathology; D015551:Autoimmunity / Q000276:immunology; D001402:B-Lymphocytes / Q000166:cytology* / Q000276:immunology* / Q000473:pathology; D016022:Case-Control Studies; D002478:Cells, Cultured; D002675:Child, Preschool; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D018655:Lymphocyte Count; D061166:Peripheral Tolerance / Q000276:immunology; D013577:Syndrome; D050378:T-Lymphocytes, Regulatory / Q000166:cytology* / Q000276:immunology / Q000473:pathology / Q000502:physiology*; D053632:X-Linked Combined Immunodeficiency Diseases / Q000276:immunology / Q000473:pathology