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

Lookup NU author(s): Dr Katherine Crossland, Dr Mario Abinun, Dr Timothy Cheetham, Professor Simon Pearce, Dr Catharien Hilkens, Dr Desa Lilic

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This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND).


Abstract

Loss-of-function mutations of the Autoimmune Regulator (AIRE) gene result 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, enabling removal of self-reactive T-cells. AIRE expression has recently been detected in myeloid dendritic cells (DC), suggesting AIRE may have a 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 that 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 in peripheral tolerance mediated by other cell types.


Publication metadata

Author(s): Crossland KL, Abinun M, Arkwright PD, Cheetham TD, Pearce SH, Hilkens CMU, Lilic D

Publication type: Article

Publication status: Published

Journal: Autoimmunity

Year: 2016

Volume: 49

Issue: 4

Pages: 211-218

Online publication date: 25/02/2016

Acceptance date: 24/01/2016

ISSN (print): 0891-6934

ISSN (electronic): 1607-842X

Publisher: Taylor & Francis

URL: http://dx.doi.org/10.3109/08916934.2016.1148692

DOI: 10.3109/08916934.2016.1148692

PubMed id: 26912174


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