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Gene expression profiling of murine innate lymphoid cells

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE46468 | GEO | 2013/04/30

SECONDARY ACCESSION(S): PRJNA200581

REPOSITORIES: GEO

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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

RNA-binding protein RBM3 negatively regulates innate lymphoid cells (ILCs) and lung inflammation

Project description:Innate lymphoid cells (ILCs) promote lung inflammation in diseases such as asthma through cytokine production. RNA-binding proteins (RBPs) are critical post-transcriptional regulators of cellular function though the role of RBPs in innate lymphoid cells is unknown. Here, we demonstrate that RNA-binding motif 3 protein (RBM3) is one of the most highly expressed RBPs in Thy1.2+ lung ILCs after fungal allergen challenge and is further induced by epithelial cytokines TSLP and IL-33 in both human and mouse ILCs. Single (rbm3-/-) and double (rbm3-/-rag2-/-) knockout mice exposed via the airway to the asthma-associated fungal allergen Alternaria alternata displayed increases in eosinophilic lung inflammation and ILC activation compared to control mice. In addition to increased Th2 cytokine production, rbm3-/- ILCs produced elevated IL-17A. The negative regulation by RBM3 in ILC responses was direct as purified rbm3-/- ILCs were hyperinflammatory in vitro and in vivo after stimulation with IL-33. Transcriptomic analysis by RNA-sequencing of rbm3-/- lung ILCs showed increased type 2 and 17 cytokines as well as global expression differences in critical cytokines, receptors, transcription factors, and survival transcripts compared with WT ILCs. Importantly, these transcript changes were independent of the numbers of AU-rich elements (AREs) which RBM3 is known to bind. Thus, regulation of ILC responses by RNA-binding proteins offers novel mechanistic insight into lung ILC biology and ILC-driven inflammatory diseases.

2021-01-01 | GSE155330 | GEO

Identification of aceNKPs, a committed common progenitor of the ILC1 and NK cell continuum

Project description:The development of innate lymphoid cell (ILC) transcription factor reporter mice has shown a previously unexpected complexity in ILC haematopoiesis. Using novel polychromic mice to achieve higher phenotypic resolution we have characterised bone marrow progenitors that are committed to the group 1 ILC lineage. These common ILC1/NK progenitors, which we call ‘aceNKPs’, are defined as lineage–Id2+IL-7Ra+CD25–a4b7–NKG2A/C/E+Bcl11b–. In vitro, aceNKPs differentiate into group 1 ILCs, including NK-like cells that express Eomes without the requirement for IL-15, and produce IFN-g and perforin upon IL-15 stimulation. Following reconstitution of Rag2–/–Il2rg–/– hosts, aceNKPs give rise to a spectrum of mature ILC1/NK cells (regardless of their tissue location) that cannot be clearly segregated into the traditional ILC1 and NK subsets, suggesting that group 1 ILCs constitute a dynamic continuum of ILCs that can develop from a common progenitor. In addition, aceNKP-derived ILC1/NK cells effectively ameliorate tumour burden in a model of lung metastasis where they acquired a cytotoxic NK cell phenotype. Our results identify the primary ILC1/NK progenitor that lacks ILC2 or ILC3 potential and is strictly committed to ILC1/NK cell production irrespective of tissue homing.

2022-11-02 | GSE213814 | GEO

Expression data from small intestinal Lin-c-Kit+Sca-1- cells and Lin-c-Kit-Sca-1- cells.

Project description:Small intestinal innate lymphoid cells (ILCs) are known to regulate intestinal epithelial cell homeostasis and to help prevent pathogenic bacterial infections, by producing IL-22. However, other functions of these cells and the lineal relationship between ILCs and lymphoid or myeloid cells have not been clear. We performed a global gene expression analysis to examine which genes are highly expressed by small intestinal ILCs (Lin-c-Kit+Sca-1- cells) compared with non-ILCs (Lin-c-Kit-Sca-1- cells). To examine the gene expression profiles of ILCs within the small intestinal lamina propria (LP), we isolated Lingeage (Lin)-c-Kit+Sca-1- cells [consisting of NKp46+ ILC22 (Lin-c-Kit+Sca-1-NKp46+ cells) and LTi-like ILC (Lin-c-Kit+Sca-1-CD4+ cells)] as the ILC population, and Lin-c-Kit-Sca-1- cells as the non-ILC population, from the small intestinal LP of 8 week-old mice by FACS, then compared the gene expression profiles between these two populations by microarray analysis.

2012-09-15 | E-GEOD-40882 | biostudies-arrayexpress

Hallmarks of primate lentiviral immunodeficiency infection recapitulate loss of innate lymphoid cells

Project description:Innate lymphoid cells (ILCs) play critical roles in mucosal barrier defense and tissue homeostasis. While ILCs are depleted in HIV-1 infection, this phenomenon is not a generalized feature of all viral infections. Here we show in untreated SIV-infected rhesus macaques (RMs) that ILC3s are lost rapidly in mesenteric lymph nodes (MLN) yet preserved in SIV+ RMs with pharmacologic or natural control of viremia. In healthy uninfected RMs, experimental depletion of CD4+ T cells in combination with DSS is sufficient to reduce ILC frequencies in the MLN. In this setting and in chronic SIV+ RMs, IL-7R alpha chain expression diminishes on ILC3s in contrast to the IL-18R alpha chain expression which remains stable. In HIV-uninfected patients with durable CD4+ T cell deficiency, deemed idiopathic CD4+ lymphopenia, similar ILC deficiencies in blood were observed, collectively identifying determinants of ILC homeostasis in primates and potential mechanisms underlying their depletion in HIV/SIV infection.

2018-11-19 | GSE116013 | 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

3D-Atlas of Group 1, Group 2 and Group 3 ILCs

Project description:We performed a multi-omic analysis of each group of ILCs to decipher ILC ontogenesis We performed Hi-C on representative cell of Group 1, Group 2 and Group 3 ILCs

2022-04-01 | GSE191309 | 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

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

CD45RA+CD62L- ILCs represent a quiescent local reservoir for the generation of mature ILC in human tissues

Project description:Innate lymphoid cells (ILCs) are highly plastic and predominantly mucosal tissue-resident cells that contribute to both homeostasis and inflammation depending on the microenvironment. The recent discovery of naïve-like tissue-resident ILCs suggests an ILC differentiation process that is akin to naïve T cell differentiation. Delineating the naïve-like ILC heterogeneity and the transcriptional, epigenetic and functional mechanisms that underlie ILC differentiation in tissues is crucial for understanding ILC biology in health and disease. Here we show that CD62L distinguishes two subsets of naïve-like CD45RA+ ILCs in tonsil tissue. While both subsets contain uni- and multipotent precursors of ILC1/NK cells and ILC3, CD62L+ ILCs resemble bona fide naïve ILCs with metabolism reminiscent of naïve T cells, lacking transcriptional and epigenetic signatures of mature ILCs. CD62L- ILCs are epigenetically similar to, but transcriptionally distinct from CD62L+ naïve-like ILCs including transcripts of cytokine signaling and metabolic pathways related to mature ILCs. A similar population of CD62L- quiescent ILCs with preferential differentiation capacity towards IL-22-producing ILC3 accumulate in the inflamed mucosa of patients with inflammatory bowel disease (IBD). These data suggest that naïve-like and quiescent ILCs are imprinted by their tissue microenvironment that poises their differentiation potential. Our findings identify restoration of homeostatic IL-22-producing ILC3 from CD62L- quiescent ILCs as a potential approach to improve tissue healing in IBD.

2022-02-17 | GSE176367 | GEO

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