Journal
SCIENCE IMMUNOLOGY
Volume 6, Issue 65, Pages -Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/sciimmunol.abl5053
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Funding
- ARCS Fellowship
- Stanford Science Fellowship
- Parker Scholar Ward
- NIH T32 FAVOR
- NIH [P01AI118688, K08230188, U01CA260852]
- ASTS Fellowship in Transplantation grant
- UCSF Sandler Fellows PSSP grant
- Cancer Research Institute Technology Impact Award
- Juvenile Diabetes Research Foundation
- Lupus Research Alliance
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The study defines eTACs at the transcriptional, genomic, and proteomic level using single-cell multiomics, transgenic murine models, and functional approaches. It reveals that eTACs consist of migratory dendritic cells expressing CCR7(+) Aire and a population coexpressing Aire and RORγt, termed Janus cells, with highly accessible chromatin and broad gene expression. Transgenic self-antigen expression by eTACs induces negative selection and prevents autoimmune diabetes, highlighting a core program influencing self-representation and tolerance in immune development.
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 gamma t (ROR gamma t) 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.
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