Single-cell multiomics defines tolerogenic extrathymic Aire-expressing populations with unique homology to thymic epithelium.

Autor:	Wang J; Diabetes Center, University of California San Francisco, San Francisco, CA, USA., Lareau CA; Department of Pathology, Stanford University, Stanford, CA, USA.; Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA., Bautista JL; Department of Surgery, University of California San Francisco, San Francisco, CA, USA., Gupta AR; Diabetes Center, University of California San Francisco, San Francisco, CA, USA.; Department of Surgery, University of California San Francisco, San Francisco, CA, USA., Sandor K; Department of Pathology, Stanford University, Stanford, CA, USA., Germino J; Diabetes Center, University of California San Francisco, San Francisco, CA, USA., Yin Y; Department of Pathology, Stanford University, Stanford, CA, USA., Arvedson MP; Diabetes Center, University of California San Francisco, San Francisco, CA, USA., Reeder GC; Diabetes Center, University of California San Francisco, San Francisco, CA, USA., Cramer NT; Diabetes Center, University of California San Francisco, San Francisco, CA, USA., Xie F; Diabetes Center, University of California San Francisco, San Francisco, CA, USA.; Department of Surgery, University of California San Francisco, San Francisco, CA, USA., Ntranos V; Diabetes Center, University of California San Francisco, San Francisco, CA, USA.; Department of Epidemiology and Biostatistics, Computational Health Sciences Institute, University of California, San Francisco, San Francisco, CA, USA., Satpathy AT; Department of Pathology, Stanford University, Stanford, CA, USA.; Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA., Anderson MS; Diabetes Center, University of California San Francisco, San Francisco, CA, USA.; Department of Medicine, University of California San Francisco, San Francisco, CA, USA., Gardner JM; Diabetes Center, University of California San Francisco, San Francisco, CA, USA.; Department of Surgery, University of California San Francisco, San Francisco, CA, USA.
Jazyk:	angličtina
Zdroj:	Science immunology [Sci Immunol] 2021 Nov 12; Vol. 6 (65), pp. eabl5053. Date of Electronic Publication: 2021 Nov 12.
DOI:	10.1126/sciimmunol.abl5053
Abstrakt:	The autoimmune regulator (Aire), a well-defined transcriptional regulator in the thymus, is also found in extrathymic Aire-expressing cells (eTACs) in the secondary lymphoid organs. eTACs are hematopoietic antigen-presenting cells and inducers of immune tolerance, but their precise identity has remained unclear. Here, we use single-cell multiomics, transgenic murine models, and functional approaches to define eTACs at the transcriptional, genomic, and proteomic level. We find that eTACs consist of two similar cell types: CCR7 + Aire-expressing migratory dendritic cells (AmDCs) and an Aire hi population coexpressing Aire and retinoic acid receptor–related orphan receptor γt (RORγt) that we term Janus cells (JCs). Both JCs and AmDCs have the highest transcriptional and genomic homology to CCR7 + migratory dendritic cells. eTACs, particularly JCs, have highly accessible chromatin and broad gene expression, including a range of tissue-specific antigens, as well as remarkable homology to medullary thymic epithelium and RANK-dependent Aire expression. Transgenic self-antigen expression by eTACs is sufficient to induce negative selection and prevent autoimmune diabetes. This transcriptional, genomic, and functional symmetry between eTACs (both JCs and AmDCs) and medullary thymic epithelium—the other principal Aire-expressing population and a key regulator of central tolerance—identifies a core program that may influence self-representation and tolerance across the spectrum of immune development.
Databáze:	MEDLINE
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