title: Regulatory T cell defect in APECED patients is associated with loss of naive FOXP3(+) precursors and impaired activated population.
abstract: The pathogenetic mechanisms of organ-specific autoimmune diseases remain obscured by the complexity of the genetic and environmental factors participating in the breakdown of tolerance. A unique opportunity to study the pathogenesis of human autoimmunity is provided by autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), a rare inherited autoimmune disease caused by mutations in Autoimmune Regulator (AIRE) gene. Loss of AIRE function disrupts the deletion of autoreactive T cells and impairs the suppressive function of regulatory T (Treg) cells. Here we show by multiparameter flow cytometry that in healthy controls the peripheral naive Treg cell subset forms a slowly dividing, persistent reservoir of recent thymic emigrants (RTEs). In APECED patients the RTE Treg cells show accelerated turnover and shift to the activated pool and the RTE reservoir is depleted. Moreover, the activated Treg cell population in the patients expresses significantly less Forkhead box protein P3 (FOXP3) than in the healthy controls, consistent with the impairment of peripheral activation. Our results indicate that in addition to their thymic effects, loss-of-function mutations in AIRE disrupt the peripheral homeostasis and activation of Treg cells. This may synergize with failed negative selection to cause APECED.
authors.affiliation: Haartman Institute, Department of Immunology, PB21, 00014 University of Helsinki, Helsinki, Finland.
authors.forename: Sini M
authors.initials: SM
authors.lastname: Laakso
authors.forename: Tuisku-Tuulia
authors.initials: TT
authors.lastname: Laurinolli
authors.forename: Laura H
authors.initials: LH
authors.lastname: Rossi
authors.forename: Anni
authors.initials: A
authors.lastname: Lehtoviita
authors.forename: Heikki
authors.initials: H
authors.lastname: Sairanen
authors.forename: Jaakko
authors.initials: J
authors.lastname: Perheentupa
authors.forename: Eliisa
authors.initials: E
authors.lastname: Kekäläinen
authors.forename: T Petteri
authors.initials: TP
authors.lastname: Arstila
mesh_terms: D000328:Adult; D002469:Cell Separation; D004252:DNA Mutational Analysis; D015536:Down-Regulation; D005260:Female; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors / Q000096:biosynthesis* / Q000235:genetics; D006706:Homeostasis; D006801:Humans; D008213:Lymphocyte Activation / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D016884:Polyendocrinopathies, Autoimmune / Q000235:genetics / Q000276:immunology; D054504:Precursor Cells, T-Lymphoid / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D014157:Transcription Factors / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D000096927:AIRE Protein
chemical_list: D051858:Forkhead Transcription Factors; D014157:Transcription Factors; D000096927:AIRE Protein; C418974:FOXP3 protein, human