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Autoimmunity. 2016 Jun;49(4):211-8. doi: 10.3109/08916934.2016.1148692. Epub 2016 Feb 25.

AIRE is not essential for the induction of human tolerogenic dendritic cells.

Author information

1
a Primary Immune Deficiency Group, Institute of Cellular Medicine, Newcastle University , Newcastle upon Tyne , UK .
2
b Department of Paediatric Immunology , Great North Children's Hospital , Newcastle upon Tyne , UK .
3
c Institute of Inflammation and Repair, University of Manchester , Manchester , UK .
4
d Department of Paediatric Endocrinology , Great North Children's Hospital , Newcastle upon Tyne , UK .
5
e Institute of Human Genetics, Newcastle University , Newcastle upon Tyne , UK .
6
f Musculoskeletal Research Group, Institute of Cellular Medicine, Newcastle University , Newcastle upon Tyne , UK , and.
7
g Department of Regional Immunology and Allergy , Newcastle upon Tyne Hospitals NHS Trust , Newcastle upon Tyne , UK.

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.

KEYWORDS:

AIRE; APECED; APS1; dendritic cells; monocyte-derived dendritic cells; tolerogenic

PMID:
26912174
DOI:
10.3109/08916934.2016.1148692
[Indexed for MEDLINE]

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