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

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Alleles
  • Autoimmunity / genetics
  • Case-Control Studies
  • Child
  • Child, Preschool
  • Cytokines / metabolism
  • Dendritic Cells / immunology*
  • Dendritic Cells / metabolism*
  • Female
  • Genotype
  • Humans
  • Immune Tolerance / genetics*
  • Male
  • Mutation
  • Phenotype
  • Polyendocrinopathies, Autoimmune / diagnosis
  • Polyendocrinopathies, Autoimmune / genetics
  • Polyendocrinopathies, Autoimmune / immunology
  • Polyendocrinopathies, Autoimmune / metabolism
  • T-Lymphocytes / immunology
  • T-Lymphocytes / metabolism
  • Transcription Factors / genetics*
  • Transcription Factors / metabolism
  • Young Adult

Substances

  • APECED protein
  • Cytokines
  • Transcription Factors