title: AIRE is not essential for the induction of human tolerogenic dendritic cells.
abstract: Loss-of-function mutations of the Autoimmune Regulator (AIRE) gene results in organ-specific autoimmunity and disease Autoimmune Polyendocrinopathy type 1 (APS1)/Autoimmune Polyendocrinopathy Candidiasis Ectodermal Dystrophy (APECED). The AIRE protein is crucial in the induction of central tolerance, promoting ectopic expression of tissue-specific antigens in medullary thymic epithelial cells and enabling removal of self-reactive T-cells. AIRE expression has recently been detected in myeloid dendritic cells (DC), suggesting AIRE may have a significant role in peripheral tolerance. DC stimulation of T-cells is critical in determining the initiation or lack of an immune response, depending on the pattern of costimulation and cytokine production by DCs, defining immunogenic/inflammatory (inflDC) and tolerogenic (tolDC) DC. In AIRE-deficient patients and healthy controls, we validated the role of AIRE in the generation and function of monocyte-derived inflDC and tolDCs by determining mRNA and protein expression of AIRE and comparing activation markers (HLA-DR/DP/DQ,CD83,CD86,CD274(PDL-1),TLR-2), cytokine production (IL-12p70,IL-10,IL-6,TNF-α,IFN-γ) and T-cell stimulatory capacity (mixed lymphocyte reaction) of AIRE+ and AIRE- DCs. We show for the first time that: (1) tolDCs from healthy individuals express AIRE; (2) AIRE expression is not significantly higher in tolDC compared to inflDC; (3) tolDC can be generated from APECED patient monocytes and (4) tolDCs lacking AIRE retain the same phenotype and reduced T-cell stimulatory function. Our findings suggest that AIRE does not have a role in the induction and function of monocyte-derived tolerogenic DC in humans, but these findings do not exclude a role for AIRE in peripheral tolerance mediated by other cell types.
authors.affiliation: a Primary Immune Deficiency Group, Institute of Cellular Medicine, Newcastle University , Newcastle upon Tyne , UK .
authors.forename: Katherine L
authors.initials: KL
authors.lastname: Crossland
authors.affiliation: a Primary Immune Deficiency Group, Institute of Cellular Medicine, Newcastle University , Newcastle upon Tyne , UK .|b Department of Paediatric Immunology , Great North Children's Hospital , Newcastle upon Tyne , UK .
authors.forename: Mario
authors.initials: M
authors.lastname: Abinun
authors.affiliation: c Institute of Inflammation and Repair, University of Manchester , Manchester , UK .
authors.forename: Peter D
authors.initials: PD
authors.lastname: Arkwright
authors.affiliation: d Department of Paediatric Endocrinology , Great North Children's Hospital , Newcastle upon Tyne , UK .
authors.forename: Timothy D
authors.initials: TD
authors.lastname: Cheetham
authors.affiliation: e Institute of Human Genetics, Newcastle University , Newcastle upon Tyne , UK .
authors.forename: Simon H
authors.initials: SH
authors.lastname: Pearce
authors.affiliation: f Musculoskeletal Research Group, Institute of Cellular Medicine, Newcastle University , Newcastle upon Tyne , UK , and.
authors.forename: Catharien M U
authors.initials: CM
authors.lastname: Hilkens
authors.affiliation: a Primary Immune Deficiency Group, Institute of Cellular Medicine, Newcastle University , Newcastle upon Tyne , UK .|g Department of Regional Immunology and Allergy , Newcastle upon Tyne Hospitals NHS Trust , Newcastle upon Tyne , UK.
authors.forename: Desa
authors.initials: D
authors.lastname: Lilic
mesh_terms: D000293:Adolescent; D000328:Adult; D000483:Alleles; D015551:Autoimmunity / Q000235:genetics; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism*; D005260:Female; D005838:Genotype; D006801:Humans; D007108:Immune Tolerance / Q000235:genetics*; D008297:Male; D009154:Mutation; D010641:Phenotype; D016884:Polyendocrinopathies, Autoimmune / Q000175:diagnosis / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D055815:Young Adult; D000096927:AIRE Protein
chemical_list: D016207:Cytokines; D014157:Transcription Factors; D000096927:AIRE Protein
keywords: AIRE; APECED; APS1; dendritic cells; monocyte-derived dendritic cells; tolerogenic