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Systemic human ILC precursors provide a substrate for tissue ILC differentiation

ABSTRACT: Innate lymphoid cells (ILC) 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 observed that a population of CD117+ ILC from peripheral blood (PB) of healthy donors does not represent any conical ILC subset, but expressed marker (CD117) commonly expressed by hemato-lymphoid progenitors. We therefore hypothesized PB CD117+ ILC might include uncommitted lymphoid precursors. In order to further understand the identity of PB CD117+ ILC, we profiled the transcriptome of highly purified circulating CD117+ ILC compared to CD34+ HSC, the latter representing immature hematopoietic progenitors with multi-lineage potential. Clear differences in gene expression profiles emerged, with a large cluster of 1540 genes expressed at substantially higher levels in CD117+ ILC. In contrast, CD34+ HSC cells highly expressed genes involved in the broad development of diverse hematopoietic lineages. Compared to HSC, CD117+ ILC express high levels of TF that have been shown to be essential for murine ILC development and we did not detect transcripts characteristic of T and B cells development. Transcriptomic analysis suggested that CD117+ ILC represent lymphoid-biased progenitors carrying a TF expression profile resembling a multi-potent ILC precursor (ILCP).

ORGANISM(S): Homo sapiens

PROVIDER: GSE90834 | GEO | 2017/03/19

SECONDARY ACCESSION(S): PRJNA356077

REPOSITORIES: GEO

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Glucocorticoids inhibit human hematopoietic stem cell differentiation toward a common ILC precursor

Project description:Background: Innate lymphoid cells (ILCs) comprise cytotoxic NK cells and “helper” ILCs (hILCs). Human hILC development is less characterized as compared to NK cells, although all ILCs are developmentally related. It has been reported that the immunosuppressive drugs glucocorticoids (GCs) regulate ILCs function, but whether they control ILCs differentiation from hematopoietic stem cells (HSCs) is unknown. Objective: We sought to analyze the effect of GCs on ILC development from HSCs. Methods: We exploited an in vitro system to generate and expand from peripheral blood (PB) HSCs a multipotent CD56+ ILC precursor able to differentiate into NK cells, ILC1s and ILC3s. We also analyzed ex vivo, at different time points, the PB of allogeneic HSC transplantation (HSCT) recipients who were or were not treated with GCs and compared ILC subset reconstitution. Results: We show that, in vitro, GCs favor the generation of NK cells from myeloid precursors, while they strongly impair lymphoid development. In support to these data, HSCT recipients who had been treated with GCs display a lower number of circulating hILCs, including the ILCP previously identified as a systemic substrate for tissue ILC differentiation. Conclusions: GCs impair the development of the CD117+ ILCP from CD34+ HSCs, while they do not affect the further steps of ILCP differentiation towards NK cells and hILC subsets. This reflects an association of GC treatment with a marked reduction of circulating hILCs in the recipients of HSCT.

2021-11-05 | GSE186950 | 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

Intestinal ILC progenitors differentially generate ILC subsets dependent on the recipient tissue microenvironment

Project description:Innate lymphoid cells (ILC) are critical in maintaining tissue homeostasis, and during infection and inflammation. Using combinatorial reporter mice we demonstrate the existence of rare, small intestinal lamina propria (siLP)- resident, ILC progenitors (siLP-ILCP) in adult mice. Transfer of siLP-ILCP into recipients generated ILC1/NK cells, ILC2 and ILC3 within the siLP microenvironment, but only ILC1/NK cells in the liver, lung and spleen. Single cell gene expression analysis confirmed the phenotype of the siLP-ILCPs and ILC progeny and indicated that siLP-ILCP-derived ILC1/NK cells from the siLP have a more tissue-resident phenotype than those from the lungs. Thus, in contrast to bone marrow-derived ILCPs, a local pool of siLP-ILCP can contribute to pan-ILC production in the intestinal microenvironment but has restricted potential in other tissues. Therefore, ILCP potential is influenced by both tissue of origin and the microenvironment during development. This may provide additional flexibility during the tuning of immune reactions.

2024-08-01 | GSE234835 | GEO

Human Innate Lymphoid Cell Precursors Express CD48 that Modulates ILC Differentiation through 2B4 Signaling

Project description:Innate lymphoid cells (ILCs) develop from common lymphoid progenitors (CLP), which further differentiate into the common ILC progenitor (CILP) that can give rise to both ILCs and NK cells. Murine ILC intermediates have recently been characterized, but the human counterparts and their developmental trajectories have not yet been identified, largely due to the lack of homologous surface receptors in both organisms. Here, we show that human CILPs (CD34+CD117+α4β7+Lin-) acquire CD48 and CD52, which define NK progenitors (NKPs) and innate lymphoid cell precursors (ILCPs). Two distinct NK cell subsets were generated in vitro from CD34+CD117+α4β7+Lin-CD48-CD52+ and CD34+CD117+α4β7+Lin-CD48+CD52+ NKPs, respectively. Independent of NKPs, ILCPs exist in the CD34+CD117+α4β7+Lin-CD48+CD52+ subset and give rise to ILC1s, ILC2s and NCR+ ILC3s, whereas CD34+CD117+α4β7+Lin-CD48+CD52- ILCPs give rise to a distinct subset of ILC3s that have lymphoid tissue inducer (LTi)-like properties. Additionally, CD48 expressing CD34+CD117+α4β7+Lin- precursors give rise to tissue-associated ILCs in vivo. We also observed that the interaction of 2B4 with CD48 induced differentiation of ILC2s, and together these findings show that expression of CD48 by human ILCPs modulates ILC differentiation.

2020-11-20 | GSE160009 | GEO

Dynamic chromatin structure during early ILC progenitor differentiation

Project description:To characterize the epigenomes during early ILC progenitor differentiation, we did DNase-seq, CUT&RUN and scMNase-seq assays in all-lymphoid progenitor (ALP), early innate lymphoid progenitor (EILP), and innate lymphoid cell progenitor (ILCP) cells.

2019-05-30 | GSE128483 | GEO

Development and differentiation of early innate lymphoid progenitors

Project description:Early innate lymphoid progenitors (EILP) have recently been identified in the mouse adult bone marrow as a multipotential progenitor population committed to ILC lineages, but their relationship with other described ILC progenitors is still unclear. In this study, we examine the progenitor-successor relationships between EILP, IL-7R+ common lymphoid progenitors (ALP), and ILC precursors (ILCp). Bioinformatic, phenotypical, functional, and genetic approaches collectively establish EILP as an intermediate progenitor between ALP and ILCp. Our work additionally provides new candidate regulators of ILC development and clearly defines the stage of requirement of transcription factors key for early ILC development.

2017-11-15 | GSE81530 | GEO

Innate lymphoid cell development requires TOX-dependent generation of a common ILC progenitor

Project description:Subtypes of innate lymphoid cells (ILC), defined by effector function and transcription factor expression, have recently been identified. In the adult, ILC derive from common lymphoid progenitors in bone marrow, although transcriptional regulation of the developmental pathways involved remains poorly defined. TOX is required for development of lymphoid tissue inducer cells, a type of ILC3 required for lymph node organogenesis, and NK cells, a type of ILC1. We show here that production of multiple ILC lineages requires TOX, as a result of TOX-dependent development of common ILC progenitors. Comparative transcriptome analysis demonstrated failure to induce various aspects of the ILC gene program in the absence of TOX, implicating this nuclear factor as a key early determinant of ILC lineage specification. TOX KO vs. wild tyype

2015-04-27 | E-GEOD-65850 | biostudies-arrayexpress

Innate lymphoid cell development requires TOX-dependent generation of a common ILC progenitor

2015-04-27 | GSE65850 | GEO

Clarification of human blood ILC subtype interrelatedness and discovery of amphiregulin production by human NK cells shed light on HIV-1 pathogenesis

Project description:Human blood innate lymphoid cells (ILCs), which include ILCs and natural killer (NK) cells, derive from a common CD117+ILC precursor (ILCP). Yet, the relationship among the ILC subsets remains unclear. Bulk and single cell RNA-Seq and ATAC-Seq showed that blood ILC subsets cluster into ILC2s, ILCPs, a mixed cluster of CD56dim and CD56– NK cells, and a separate cluster of CD56hiNK cells that shares features with both ILCs and CD56dim/–NK cells. In surprising contrast to mice, tissue repair protein amphiregulin (AREG) was produced by human NK cells, with even higher levels in CD56hiNK cells than in ILCs. AREG expression in NK cells was driven by TCF7/WNT signaling and inhibited by TGFB1, a cytokine elevated in HIV-1+ people. Knockout of RUNX3, a WNT antagonist acting downstream of TGFB1, increased AREG production. Consistent with these findings, AREG+NK cells were decreased in people living with HIV-1. Additionally, functionally defective CD56–NK cells expanded in HIV-1+ people, in inverse correlation with CD56dimNK cells, ILCs, and CD4+T cells. Experiments in tissue culture and in humanized mice showed that CD56–NK cells derive from the epigenetically similar CD56dimNK cells, and that stimulation of MTOR by CD4+T cells or exogenous IL-2 prevents their expansion. These findings clarify how ILC subsets are related to each other and provide insight into how HIV-1 infection disrupts ILC homeostasis and contributes to pathology

2023-06-07 | GSE203002 | GEO

A lineage commitment checkpoint in early ILC development [bulk RNA-seq]

Project description:Understanding how cellular function is imprinted during development requires the identification of factors controlling lineage specification and commitment, and the intermediate progenitors in which they act. Using population level and single cell approaches, we examine transcriptional and functional heterogeneity within early innate lymphoid cells (ILC) progenitors. We identify a developmental bifurcation toward dendritic cell fate that reveals the uncommitted state of early specified ILC progenitors. We subsequently characterize an ILC-commitment checkpoint controlled by the transcription factor TCF-1. The present study reveals unexpected heterogeneity within early innate progenitor populations, and characterizes lineage infidelity that accompanies early ILC specification prior to commitment.

2019-04-22 | GSE113765 | GEO

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