Age-related disruption of steady-state thymic medulla provokes autoimmune phenotype via perturbing negative selection

Jiangyan Xia, Hongjun Wang, Jianfei Guo, Zhijie Zhang, Brandon Coder, Dong Ming Su

Research output: Contribution to journalArticlepeer-review

24 Scopus citations

Abstract

The hymic medulla plays an essential role in the generation of central tolerance by eliminating self-reactive T-cell clones through thymic negative selection and developing natural regulatory T cells. Age-related FoxN1 decline induces disruption of medullary thymic epithelial cells (mTECs). However, it is unknown whether this perturbs central tolerance to increase autoimmune predisposition in the elderly. Using a loxP-floxed-FoxN1 (FoxN1flox) mouse model, which exhibits a spontaneous ubiquitous deletion of FoxN1 with age to accelerate thymic aging, we investigated whether disruption of steady-state thymic medulla results in an increase of autoimmune-prone associated with age. We demonstrated age-associated ubiquitous loss of FoxN1flox-formed two-dimensional thymic epithelial cysts were primarily located in the medulla. This resulted in disruption of thymic medullary steady state, with evidence of perturbed negative selection, including reduced expression of the autoimmune regulator (Aire) gene and disrupted accumulation of thymic dendritic cells in the medulla, which are required for negative selection. These provoke autoimmune phenotypes, including increased inflammatory cell infiltration in multiple organs in these mice. This finding in an animal model provides a mechanistic explanation of increased susceptibility to autoimmunity in aged humans, although they may not show clinic manifestations without induction.

Original languageEnglish
Pages (from-to)248-259
Number of pages12
JournalAging and Disease
Volume3
Issue number3
StatePublished - 1 Jan 2012

Keywords

  • Aging
  • Autoimmunity
  • Central immunological tolerance
  • FoxN1 gene
  • Negative selection
  • Thymic microstructure

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