Tissue-specific transcriptional imprinting and heterogeneity in human innate lymphoid cells revealed by full-length single-cell RNA-sequencing

Mazzurana, Luca; Czarnewski, Paulo; Jönsson, Viktor; Wigge, Leif; Ringnér, Markus; Williams, Teresa C.; Ravindran, Avinash; Björklund, Åsa K.; Säfholm, Jesper; Nilsson, Gunnar; Dahlén, Sven Erik; Orre, Ann Charlotte; Al‐Ameri, Mamdoh; Höög, Charlotte; Hedin, Charlotte; Szczegielniak, Sylwester; Almér, Sven; Mjösberg, Jenny

doi:10.1038/s41422-020-00445-x

Cited by 125 publications

(173 citation statements)

References 65 publications

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“…Further evidence for TCR gene rearrangements in other ILC subsets has recently been demonstrated in human studies through sophisticated single-cell transcriptome analyses that revealed gene expression patterns associated with tissueresidency and migration in human ILCs (66). In this report, blood ILC1s (EOMES -/+ ) are shown to uphold the expression of T-cell related-genes such as CD3, CD4, CD5, CD6, CD27, LEF1.…”

Section: Tcr Gene Rearrangements In Ilcsmentioning

confidence: 63%

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ILC-You in the Thymus: A Fresh Look at Innate Lymphoid Cell Development

Shin

McNagny

2021

Front. Immunol.

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The discovery of innate lymphoid cells (ILCs) has revolutionized our understanding of innate immunity and immune cell interactions at epithelial barrier sites. Their presence and maintenance are critical for modulating immune homeostasis, responding to injury or infection, and repairing damaged tissues. To date, ILCs have been defined by a set of transcription factors, surface antigens and cytokines, and their functions resemble those of three major classes of helper T cell subsets, Th1, Th2 and Th17. Despite this, the lack of antigen-specific surface receptors and the notion that ILCs can develop in the absence of the thymic niche have clearly set them apart from the T-cell lineage and promulgated a dogma that ILCs develop directly from progenitors in the bone marrow. Interestingly however, emerging studies have challenged the BM-centric view of adult ILC development and suggest that ILCs could arise neonatally from developing T cell progenitors. In this review, we discuss ILC development in parallel to T-cell development and summarize key findings that support a T-cell-centric view of ILC ontogeny.

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Section: Tcr Gene Rearrangements In Ilcsmentioning

confidence: 63%

“…with CXCR3 + Th1 cells (66). These observations suggest that ILC1s are more akin to CD4 + and CD8 + T cells and that in their lifetime, they have undergone a maturation process in the thymus.…”

Section: Tcr Gene Rearrangements In Ilcsmentioning

confidence: 81%

ILC-You in the Thymus: A Fresh Look at Innate Lymphoid Cell Development

Shin

McNagny

2021

Front. Immunol.

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“…MAIT cells expressed TRAV1, TRAV2 and SLC4A10 . ILC2 expressed PTGDR2, HPGDS, IL1RL1 and KRT1 64 and were found in the fetal samples.…”

Section: Methodsmentioning

confidence: 94%

Cells of the human intestinal tract mapped across space and time

Elmentaite

Kumasaka

Roberts

et al. 2021

Nature

397

349

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The cellular landscape of the human intestinal tract is dynamic throughout life, developing in utero and changing in response to functional requirements and environmental exposures. Here, to comprehensively map cell lineages, we use single-cell RNA sequencing and antigen receptor analysis of almost half a million cells from up to 5 anatomical regions in the developing and up to 11 distinct anatomical regions in the healthy paediatric and adult human gut. This reveals the existence of transcriptionally distinct BEST4 epithelial cells throughout the human intestinal tract. Furthermore, we implicate IgG sensing as a function of intestinal tuft cells. We describe neural cell populations in the developing enteric nervous system, and predict cell-type-specific expression of genes associated with Hirschsprung’s disease. Finally, using a systems approach, we identify key cell players that drive the formation of secondary lymphoid tissue in early human development. We show that these programs are adopted in inflammatory bowel disease to recruit and retain immune cells at the site of inflammation. This catalogue of intestinal cells will provide new insights into cellular programs in development, homeostasis and disease.

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“…Mouse lung ILC2s are relatively insensitive to IL-25 compared with IL-33 ( 28 ) due to low expression of the receptor ( 29 ). Although tissue-specific receptor expression and cytokine sensitivity in human ILC2s are not fully established ( 14 , 30 , 31 ), such data would inform cytokine candidacy for induction of EGPA in patients and reveal patient-specific correlations between individual tissue cytokine changes and specific organ involvement.…”

Section: Discussionmentioning

confidence: 99%

A role for IL-33–activated ILC2s in eosinophilic vasculitis

Kotas¹,

Dion²,

Dyken³

et al. 2021

JCI Insight

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Eosinophilic granulomatosis with polyangiitis (EGPA) is a rare but serious disease with poorly understood mechanisms. Here we report that patients with EGPA have elevated levels of TSLP, IL-25, and sST2, well characterized cytokine "alarmins" that activate or modulate type 2 innate lymphoid cells (ILC2s). Patients with active EGPA have a concurrent reduction in circulating ILC2s, suggesting a role for ILC2s in the pathogenesis of this disease. To explore the mechanism of these findings in patients, we established a model of EGPA in which active vasculitis and pulmonary hemorrhage are induced by IL-33 administration in predisposed, hypereosinophilic mice. In this model, induction of pulmonary hemorrhage and vasculitis is dependent on ILC2s and signaling through IL4R. In the absence of IL4R or STAT6, IL-33treated mice have less vascular leak and pulmonary edema, less endothelial activation, and reduced eotaxin production, cumulatively leading to a reduction of pathologic eosinophil migration into the lung parenchyma. These results offer a mouse model for use in future mechanistic studies of EGPA, and suggest that IL-33, ILC2s and IL4R signaling may be potential targets for further study and therapeutic targeting in patients with EGPA.

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Tissue-specific transcriptional imprinting and heterogeneity in human innate lymphoid cells revealed by full-length single-cell RNA-sequencing

Cited by 125 publications

References 65 publications

ILC-You in the Thymus: A Fresh Look at Innate Lymphoid Cell Development

ILC-You in the Thymus: A Fresh Look at Innate Lymphoid Cell Development

Cells of the human intestinal tract mapped across space and time

A role for IL-33–activated ILC2s in eosinophilic vasculitis

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