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

ABSTRACT: The impact of the microenvironment on innate lymphoid cell (ILC)-mediated immunity in humans remains largely unknown. Here we used full-length Smart-seq2 single-cell RNA-sequencing to unravel tissue-specific transcriptional profiles and heterogeneity of CD127+ ILCs across four human tissues. Correlation analysis identified gene modules characterizing the migratory properties of tonsil and blood ILCs, and signatures of tissue-residency, activation and modified metabolism in gut and lung ILCs. Trajectory analysis revealed potential differentiation pathways from circulating and tissue-resident naïve ILCs to a spectrum of mature ILC subsets. In the lung we identified both CRTH2+ and CRTH2- ILC2 with lung-specific signatures, which could be recapitulated by alarmin-exposure of circulating ILC2. Finally, we describe unique TCR-V(D)J-rearrangement patterns of blood ILC1-like cells, revealing a subset of potentially immature ILCs with TCR-d rearrangement. In summary, we provide publicly available data as a resource for in-depth understanding of ILC-mediated immunity in humans, with implications for disease.

ORGANISM(S): Homo sapiens

PROVIDER: GSE150050 | GEO | 2020/12/14

REPOSITORIES: GEO

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Single-cell deciphering of human fetal innate lymphoid cell development

Project description:The functions of innate lymphoid cells (ILCs) in immune system are increasingly appreciated, whereas the early development of ILCs in human remains elusive. In this study, we sorted humanhematopoietic stem progenitor cells, lymphoid progenitors, presumed ILC progenitor/precursors and mature ILCs in the fetal hematopoietic, lymphoid and non-lymphoid tissues, from 8 to 12 PCW,for single-cell RNA-sequencing, followed by computational analysis and functional validation. We delineated the early phase of ILC development, from hematopoietic stem progenitor cells to multipotent lymphoid progenitors and to ILC progenitors, which mainly occurred in fetal liver and intestine. We further unveiled interleukin-3 receptor alpha (IL-3RA) as the surface marker for the lymphoid progenitors with T cell, B cell and ILC potentials. Notably, we determined the heterogeneity and tissue distribution of each ILC subpopulation, revealing the shared proliferating characteristics of the precursors of each ILC subtype. Additionally, a novel unconventional ILC2 subpopulation (CRTH2-CCR9+ ILC2) was identified in fetal thymus. Taken together, our study illuminates the precise cellular and molecular features underlying the stepwise formation of human fetal ILC hierarchy with remarkable spatiotemporal heterogeneity.

2021-08-09 | GSE163587 | GEO

Comprehensive protein-expression map of ILC2 and ILC3 subsets in healthy human skin

Project description:Innate lymphoid cells (ILCs) have emerged as essential players in the skin-associated immune system in health and inflammatory skin diseases. Their low numbers and lack of specific markers hampered extensive characterization and consequently resulted in limited knowledge of their protein expression. Here, we combined flow cytometry and state-of-the-art proteomics to comprehensively describe the proteins constitutively expressed by ILC2 and ILC3 subsets derived from healthy human skin and peripheral blood. We quantified 6666 proteins from skin ILC and identified 608 differentially expressed proteins in the investigated subsets. In addition to the current analyses, highlighting new functions of ILC, the ILC proteomic libraries and the proteomes of the ILC2 and ILC3 subsets will serve as valuable resources for future analyses of ILC function and are available at http://skin.science.

2023-10-10 | PXD037817 | Pride

In Situ Maturation and Tissue Adaptation of Type 2 Innate Lymphoid Cell Progenitors

Project description:We analyzed the full spectrum of lung ILC2s at single-cell transcriptome resolution and identified an immature population of Il18r1+ tissue-associated ILCs, that express Tcf7 and Zbtb16, transcription factors known to act in ILC progenitors, and low levels of Gata3, ST2 and ILC2 effector molecules. We revealed a continuous differentiation trajectory and validated the potential of immature Il18r1+ cells to differentiate into Gata3hi ILC2s. We found that immature ILCs were recruited into the adult lung of parabiotic and shield chimeric mice during helminth infection. Intriguingly, recruited cells generated the entire spectrum of ILC2s in the lung, consistent with their potential role in the renewal of tissue ILC2s. Our work identifies local ILC progenitors and highlights their tissue adaptation and in situ differentiation as a mechanism of ILC maintenance and phenotypic diversification

2020-10-02 | GSE141330 | GEO

Systemic human ILC precursors provide a substrate for tissue ILC differentiation

Project description:Innate lymphoid cells (ILCs) represent innate versions of T helper and cytotoxic T cells that differentiate from committed ILC precursors (ILCP). Still, how ILCP relate to mature tissue-resident ILCs remains unclear. We identify ILCP that are present in the blood and all tested lymphoid and non-lymphoid human tissues. Human ILCP fail to express the signature transcription factors (TF) and cytokine outputs of mature NK cells and ILCs but are epigenetically poised to do so. Human ILCP robustly generate all ILC subsets in vitro and in vivo. While human ILCP express RAR related orphan receptor C (RORC), circulating ILCP can be found in RORC-deficient patients that retain potential for EOMES+ NK cells, T-BET+ ILC1, GATA-3+ ILC2 and for IL-22+ but not for IL-17A+ ILC3. We propose a model of tissue ILC differentiation (‘ILC-poiesis’) whereby diverse ILC subsets are generated in situ from ILCP in response to environmental stressors, inflammation and infection.

2017-03-19 | GSE90640 | GEO

Characterization of rat ILCs reveals ILC2 as the dominant intestinal subset

Project description:Innate lymphoid cells (ILCs) are tissue-resident lymphocytes that lack antigen-specific receptors and exhibit innate effector functions such as cytokine production that play an important role in immediate responses to pathogens especially at mucosal sites. Mouse and human ILC subsets have been extensively characterized in various tissues and in blood. In this study, we present the first characterization of ILCs and ILC subsets in rat gut and secondary lymphoid organs. ScRNAseq and flow cytometric data shows that phenotype and function of rat ILC subsets are conserved similar to human and mouse ILCs. However, contrary to human and mouse, our study unexpectedly revealed that ILC2 and not ILC3 was by far the dominant ILC subset in the rat intestinal lamina propria. ILC2 predominance in the gut was independent of rat strain, sex or housing facility. In contrast, ILC3 were the main ILC subset in mesenteric lymph nodes and Peyer patches, in which strain-dependent differences in ILC frequencies were also observed. In conclusion, our study demonstrates that in spite of highly conserved phenotype and function between mice, rat and humans, the distribution of ILC subsets in the intestinal mucosa is species-dependent, likely in response to both genetic and environmental factors.

2020-02-12 | GSE143920 | GEO

Gene expression profiling of murine innate lymphoid cells

Project description:Innate lymphoid cells (ILCs) are a recently recognized heterogenous group of immune cells that are critical in orchestrating immunity and inflammation in the intestine, but whether ILCs influence immune responses or tissue homeostasis at other mucosal sites remains poorly characterized. Here we identify a population of lung-resident ILCs in mice and humans that expressed the alloantigen Thy-1 (CD90), interleukin 2 (IL-2) receptor a-chain (CD25), IL-7 receptor a-chain (CD127) and the IL-33 receptor subunit T1-ST2. Notably, mouse ILCs accumulated in the lung after infection with influenza virus, and depletion of ILCs resulted in loss of airway epithelial integrity, diminished lung function and impaired airway remodeling. These defects were restored by administration of the lung ILC product amphiregulin. Collectively, our results demonstrate a critical role for lung ILCs in restoring airway epithelial integrity and tissue homeostasis after infection with influenza virus. As part of this study, we performed gene expression profiling to examine how the transcriptional signatures compared between murine naïve group 2 lung ILC and group 3 splenic LTi cell populations. Group 2 ILCs from the lung (Lin- CD90+ CD25+ T1/ST2+) and Group 3 LTi cells from the spleen (Lin- CD90+ CD25+ CD4+) were sort-purified from naive wildtype C57BL/6 mice using BD FACS Aria. Four biological replicates were collected, each replicate containing 1.5 x 104 to 2 x104 cells sorted to a purity >97% from six pooled lungs (ILCs) or 10 pooled spleens (LTi cells). Cells were sorted directly into TRIzol LS (Invitrogen), then mRNA was isolated, amplified, labeled, and hybridized to Affymetrix GeneChip (Mouse Gene 1.0 ST).

2013-04-30 | E-GEOD-46468 | biostudies-arrayexpress

Dynamic single-cell regulomes characterize human peripheral blood ILC subpopulations [scRNA-seq]

Project description:Innate lymphoid cells (ILCs) are highly plastic immune cells that have been separated into 3 main subsets, characterized by distinct phenotypic and functional profiles. Using single cell approaches, heightened heterogeneity of mouse ILCs has been recently appreciated, imprinted by tissue signals that shape their transcriptome and epigenome. Intra-subset diversity has also been observed in human ILCs. However, combined transcriptomic and epigenetic analyses of single ILCs in humans are lacking. Here we show high transcriptional and epigenetic heterogeneity among human circulating ILCs in healthy individuals. We describe phenotypically distinct subclusters within main circulating ILC populations. We show diverse chromatin accessibility within main ILC subsets, compatible with differentially poised states. We validate the use of this healthy donor-based analysis as resource dataset to infer ILC changes occurring in disease conditions. Overall, our work provides new insights in the complex human ILC biology. We anticipate our work to be a starting point to facilitate hypothesis-driven studies in patients, without the need to perform single cell OMICs using precious patients’ material

2023-09-01 | GSE225168 | GEO

Dynamic single-cell regulomes characterize human peripheral blood ILC subpopulations [scATAC-seq]

2023-09-01 | GSE225167 | GEO

Gene expression profiling of murine innate lymphoid cells

2013-04-30 | GSE46468 | GEO

Unconventional ST2- and CD127-negative lung ILC2 populations are induced by Alternaria

Project description:Background: Alternaria exposure is associated with severe asthma in humans. Alternaria exposure in mice potently activates group 2 innate lymphoid cells (ILC2s) via the IL-33/ST2 axis and causes ILC2s to robustly secrete type 2 cytokines. Objective: Our aim was to determine whether conventionally used ILC2 markers, ST2 (IL-33R) and CD127 (IL-7Ra), were sufficient to identify all Th2-cytokine producing ILCs after Alternaria exposure. Methods: Mice received intranasal Alternaria for three days prior to analysis. Lung ILCs were identified by flow cytometry as CD45+Lineage−Thy1.2+ lymphocyte-sized cells, divided into four subsets based on ST2 and CD127 expression, and stained for intracellular cytokines and transcription factors. Sort-purified ILC subpopulations were also analyzed by RNA sequencing and qPCR. Results: Alternaria exposure led to accumulation of all ILC populations regardless of ST2 or CD127 expression. Nearly half of the GATA-3+, IL-5+, and IL-13+ ILCs were “unconventional” as they were either single or double negative for ST2/CD127. Further, these populations upregulated CD25, KLRG1, and ICOS after Alternaria challenge. Some activated unconventional IL-5+ ILC2s also produced IFNγ and IL-17A. In addition to shared ILC2 transcripts (Gata3, Il5, Il13) in all populations, RNA-seq further identified novel transcripts enriched in each subset. Finally, transcripts from all populations that correlated best with IL-5 and IL-13 production included Tnfrsf18, Ffar2, and Pde4b. Conclusions: Unconventional ST2- and CD127-negative mouse lung ILC2 populations are induced by Alternaria. Thus, commonly used lung ILC2 identification methods based on ST2 and CD127 do not accurately account for the total ILC2 burden and may exclude nearly half of these cells.

2019-08-22 | GSE136156 | GEO

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