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

Wang, Jiaxi; Lareau, Caleb A.; Bautista, Jhoanne L.; Gupta, Alexander R; Sandor, Katalin; Germino, Joe; Yin, Yijun; Arvedson, Matthew P.; Reeder, Gabriella C.; Cramer, Nathan T.; Xie, Fang; Ntranos, Vasilis; Satpathy, Ansuman T.; Anderson, Mark S.; Gardner, James M.

doi:10.1126/sciimmunol.abl5053

Cited by 45 publications

(55 citation statements)

References 66 publications

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“…2E ). Extra-thymic expression of the autoimmune regulator AIRE has been reported in humans ( 39 , 40 ), however, its functional role in secondary lymphoid organs remains poorly understood and is a matter of intense research ( 41 – 43 ). We validated the presence of migDCs in lung-draining lymph nodes by immunofluorescence ( fig.…”

Section: Resultsmentioning

confidence: 99%

Cross-tissue immune cell analysis reveals tissue-specific features in humans

Conde

Jarvis

et al. 2022

Science

425

418

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Despite their crucial role in health and disease, our knowledge of immune cells within human tissues remains limited. We surveyed the immune compartment of 16 tissues from 12 adult donors by single-cell RNA sequencing and VDJ sequencing generating a dataset of ~360,000 cells. To systematically resolve immune cell heterogeneity across tissues, we developed CellTypist, a machine learning tool for rapid and precise cell type annotation. Using this approach, combined with detailed curation, we determined the tissue distribution of finely phenotyped immune cell types, revealing hitherto unappreciated tissue-specific features and clonal architecture of T and B cells. Our multitissue approach lays the foundation for identifying highly resolved immune cell types by leveraging a common reference dataset, tissue-integrated expression analysis, and antigen receptor sequencing.

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Section: Resultsmentioning

confidence: 99%

Cross-tissue immune cell analysis reveals tissue-specific features in humans

Conde

Jarvis

et al. 2022

Science

425

418

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“…However, in contrast to the thymus, we could not assign a specific DC origin to each aDC subset (Figure S9B). Noteworthy, aDC2 expressed shallow levels of Autoimmune Regulator (AIRE; Figure 6B), which has a role in upregulating tissue-specific antigens to generate peripheral tolerance (Gardner et al, 2013;Poliani et al, 2010;Wang et al, 2021). Finally, we annotated four clusters as monocytes (VCAN, S100A12), M1 macrophages (TNIP3), mast cells (TPSAB1, TPSB2) and neutrophils (CXCL8, PI3).…”

Section: Non-lymphoid Cells and Novel Roles Of Slancyte Subsets In Hu...mentioning

confidence: 99%

An Atlas of Cells in the Human Tonsil

Massoni-Badosa

Soler-Vila

Aguilar-Fernández

et al. 2022

Preprint

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Palatine tonsils are secondary lymphoid organs representing the first line of immunological defense against inhaled or ingested pathogens. Here, we present a comprehensive census of cell types forming the human tonsil by applying single-cell transcriptome, epigenome, proteome and adaptive immune repertoire sequencing as well as spatial transcriptomics, resulting in an atlas of >357,000 cells. We provide a glossary of 121 annotated cell types and states, and disentangle gene regulatory mechanisms that drive cells through specialized lineage trajectories. Exemplarily, we stratify multiple tonsil-resident myeloid slancyte subtypes, establish a distant BCL6 superenhancer as locally active in both follicle-associated T and B cells, and describe SIX5 as a potentially novel transcriptional regulator of plasma cell maturation. Further, our atlas is a reference map to understand alterations observed in disease. Here, we discover immune-phenotype plasticity in tumoral cells and microenvironment shifts of mantle cell lymphomas (MCL). To facilitate such reference-based analysis, we develop HCATonsilData and SLOcatoR, a computational framework that provides programmatic and modular access to our dataset; and allows the straightforward annotation of future single-cell profiles from secondary lymphoid organs.

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“…In the intestine, CD103 + DCs are recognized as a key DC subset supporting tolerance to commensal bacteria via peripheral induction of Tregs (Coombes et al, 2007). More recently, Aire-expressing DCs in the intestinal lymph nodes have been identified as an important cell type contributing to this function (Akagbosu et al, 2022;Wang et al, 2021). While further investigation is needed to understand potential overlapping features and functions between CD301b + DC2 and these DC subsets, initial evidence supports that there is some degree of barrier site-specific restriction of this function to distinct DC types.…”

Section: Discussionmentioning

confidence: 99%

Early life tolerance depends on a subset of specialized dendritic cells and is reinforced by the skin microbiota

Weckel

Dhariwala

et al. 2022

Preprint

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Early life establishment of tolerance to commensal bacteria at barrier surfaces carries enduring implications for immune health but remains poorly understood. Here we show that this process is controlled by microbial interaction with a specialized subset of antigen presenting cells. More particularly, we identify CD301b+ type 2 conventional dendritic cells (DC) as a subset in neonatal skin specifically capable of uptake, presentation and generation of regulatory T cells (Tregs) to commensal antigens. In early life, CD301b+ DC2 are enriched for programs of phagocytosis and maturation, while also expressing tolerogenic markers. In both human and murine skin, these signatures were reinforced by microbial uptake. In contrast to their adult counterparts or other early life DC subsets, neonatal CD301b+ DC2 highly expressed the retinoic acid-producing enzyme, RALDH2, deletion of which limited commensal-specific Tregs. Thus, synergistic interactions between bacteria and a specialized DC subset critically support early life tolerance at the cutaneous interface.

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

Abstract: Extrathymic Aire-expressing cells are hematopoietic migratory DC–like populations with homology to medullary thymic epithelium.

Cited by 45 publications

References 66 publications

Cross-tissue immune cell analysis reveals tissue-specific features in humans

Cross-tissue immune cell analysis reveals tissue-specific features in humans

An Atlas of Cells in the Human Tonsil

Early life tolerance depends on a subset of specialized dendritic cells and is reinforced by the skin microbiota

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