Deletional Tolerance Mediated by Extrathymic Aire-Expressing Cells

Abstract

The prevention of autoimmunity requires elimination of self-reactive T cells during their development and maturation. Expression of diverse self-antigens by stromal cells in the thymus is essential to this process, and depends, in part, on the activity of the Autoimmune Regulator (Aire) gene. Here we report the identification of extrathymic Aire-expressing cells (eTACs) resident within the secondary lymphoid organs. These stromally-derived eTACs express a diverse array of unique self-antigens and are capable of interacting with and deleting naïve autoreactive T cells. Using twophoton microscopy we observe stable, antigen-specific interactions between eTACs and autoreactive T cells. We propose that such a secondary network of self-antigen-expressing stromal cells may help reinforce immune tolerance by preventing the maturation of autoreactive T cells that escape thymic negative selection.

Autoimmune regulator (AIRE)-deficient CD8+CD28lowregulatory T lymphocytes fail to control experimental colitis

“…Also, lymph node stromal cells have been reported to express AIRE, to transcribe a distinct subset of genes encoding tissue-restricted antigens, and to induce peripheral tolerance (45)(46)(47)(48)(49). We have found mature CD8 + CD28 low T cells in the thymus, suggesting that they may develop in this primary lymphoid organ (Fig.…”

Thymosin α1: burying secrets in the thymus

“…Although these results reveal a role of thymic AIRE, self-tolerance must continue to be enforced after T cells leave the thymus. In this regard, human peripheral lymphoid tissues contain AIRE-expressing DCs [31] and a population of extrathymic AIRE-expressing cells (eTACs) that may play an important and previously uncharacterized role in self-tolerance have been described [32]. The eTACs share certain characteristics with mTECs, including being equipped to act as professional antigen-presenting cells and the AIRE-regulated expression of TSAs.…”

Autonomous role of medullary thymic epithelial cells in central CD4+ T cell tolerance

“…To facilitate the phenotypic distinction of mTEC subsets, we crossed C2TAkd mice with AIRE-reporter (Adig) mice, in which green fluorescent protein (GFP) is expressed from a modified Aire locus 29 . We analyzed the abundance of the properly processed C2TAkd miRNA and of the Aire mRNA in purified thymic stromal cells using a custom miRNA TaqMan assay or quantitative RT-PCR, respectively.…”