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Deletional tolerance mediated by extrathymic Aire-expressing cells.

ABSTRACT: The prevention of autoimmunity requires the elimination of self-reactive T cells during their development and maturation. The 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 distinct self-antigens and are capable of interacting with and deleting naïve autoreactive T cells. Using two-photon microscopy, we observed 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.

SUBMITTER: Gardner JM

PROVIDER: S-EPMC2532844 | biostudies-literature | 2008 Aug

REPOSITORIES: biostudies-literature

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Deletional tolerance mediated by extrathymic Aire-expressing cells.

Gardner James M JM Devoss Jason J JJ Friedman Rachel S RS Wong David J DJ Tan Ying X YX Zhou Xuyu X Johannes Kellsey P KP Su Maureen A MA Chang Howard Y HY Krummel Matthew F MF Anderson Mark S MS

Science (New York, N.Y.) 20080801 5890

The prevention of autoimmunity requires the elimination of self-reactive T cells during their development and maturation. The 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 distinct self-an ...[more]

PMID: 18687966

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Project description:Adaptive immunity requires multiple complementary mechanisms to maintain self-tolerance. Dedicated tolerogenic lymphoid populations and their key transcriptional regulators have been well characterized, but while recent evidence suggests some myeloid populations, particularly migratory dendritic cells (migDCs), may have similar functions, the identity of these populations and the transcriptional circuits regulating them remain obscure. The Autoimmune Regulator (Aire), well defined in medullary thymic epithelial cells (mTECs), is also expressed in extrathymic Aire-expressing cells (eTACs) in the secondary lymphoid organs. eTACs have been shown to have tolerogenic capabilities (ref), and recently work has shown them to be required for normal immune homeostasis in pregnancy (ref). But the precise identity and function of these cells remain unclear. Here using high-dimensional single-cell multiomics (scRNAseq/ASAPseq), we define the identity and biology of the principal extrathymic Aire-expressing populations at the transcriptional, genomic, and proteomic level, resulting in two related populations: CCR7+ Aire-regulated migratory dendritic cells (ArmDCs) and a novel population co-expressing RAR-related orphan receptor gamma-t (ROR-γt), with significant transcriptional and genomic homology to both migDCs and mTECs, which we termed Janus cells (JCs). We demonstrate these eTAC populations share a distinct transcriptional and genomic homology to medullary epithelium and, like mTECs, depend on RANK-RANK-ligand interactions to drive Aire expression. Lineage-tracing experiments suggest JCs are not a precursor population to the majority of ArmDCs. Further, self-antigen display by eTACs is sufficient to mediate negative selection of T cells that escape thymic selection. This remarkable central and peripheral homology suggests that a core Aire-associated transcriptional program may drive immune tolerance in both the thymus and periphery, and suggests a remarkable convergence of transcriptional programs in two disparate cell lineages in the thymus and periphery.

Dataset Information

Deletional tolerance mediated by extrathymic Aire-expressing cells.

Publications

Deletional tolerance mediated by extrathymic Aire-expressing cells.

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