Development and differentiation of early innate lymphoid progenitors

Harly, Christelle; Cam, Maggie; Kaye, Jonathan; Bhandoola, Avinash

doi:10.1084/jem.20170832

Cited by 88 publications

(144 citation statements)

References 54 publications

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“…Lmo4 is also involved in the tumorigenesis of pancreatic cancer (Yu et al, 2008) and non–small cell lung cancer (Wang et al, 2016). Several studies reported that Lmo4 is highly expressed in ILCs and their progenitors (Robinette et al, 2015; Gury-BenAri et al, 2016; Seillet et al, 2016; Harly et al, 2018). Of note, Lmo4 can interact with LIM domain binding 1 to form a dimer that regulates gene transcription (Deane et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

Yeats4 drives ILC lineage commitment via activation of Lmo4 transcription

Liu

Yang

Zhu

et al. 2019

Journal of Experimental Medicine

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Innate lymphoid cells (ILCs) play critical roles in defending infections and maintaining mucosal homeostasis. All ILCs arise from common lymphoid progenitors (CLPs) in bone marrow. However, how CLPs stratify and differentiate into ILC lineages remains elusive. Here, we showed that Yeats4 is highly expressed in ILCs and their progenitors. Yeats4 conditional KO in the hematopoietic system causes decreased numbers of ILCs and impairs their effector functions. Moreover, Yeats4 regulates α4β7+ CLP differentiation toward common helper ILC progenitors (CHILPs). Mechanistically, Yeats4 recruits the Dot1l–RNA Pol II complex onto Lmo4 promoter through recognizing H3K27ac modification to initiate Lmo4 transcription in α4β7+ CLPs. Additionally, Lmo4 deficiency also impairs ILC lineage differentiation and their effector functions. Collectively, the Yeats4–Lmo4 axis is required for ILC lineage commitment.

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Section: Discussionmentioning

confidence: 99%

Yeats4 drives ILC lineage commitment via activation of Lmo4 transcription

Liu

Yang

Zhu

et al. 2019

Journal of Experimental Medicine

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“…ILCs develop from ILC progenitors (ILCPs) in the bone marrow (BM; Yang et al, 2015; Klose et al, 2014; Constantinides et al, 2014; Xu et al, 2019; Walker et al, 2019). These BM progenitors differentiate along the ILC lineage as they gradually up-regulate the transcription factors TCF-1 (encoded by Tcf7 ), TOX ( Tox ), ID2 ( Id2 ), and PLZF ( Zbtb16 ; Yu et al, 2016; Ishizuka et al, 2016; Harly et al, 2018). ILC2-restricted progenitors termed ILC2 progenitors (ILC2Ps) have also been found in the BM (Halim et al, 2012b; Hoyler et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

“…To study lung ILC2 heterogeneity, we generated an ILC(2) lineage tracer mouse model based on the expression of the transcription factor RORα. Rorα is expressed in early ILCPs (Constantinides et al, 2014; Harly et al, 2018; Ishizuka et al, 2016; Lim et al, 2017) and mature ILCs (Robinette et al, 2015; Halim et al, 2012b; Wong et al, 2012; Lo et al, 2016; Hoyler et al, 2012). Therefore, RORα lineage tracer mice enabled us to identify ILCPs and mature ILC2s in the lung without relying on their expression of cell surface markers, specific cytokines, or enzymes.…”

Section: Introductionmentioning

confidence: 99%

Single-cell analysis of RORα tracer mouse lung reveals ILC progenitors and effector ILC2 subsets

Ghaedi

Shen

Orangi

et al. 2019

Journal of Experimental Medicine

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Lung group 2 innate lymphoid cells (ILC2s) drive allergic inflammation and promote tissue repair. ILC2 development is dependent on the transcription factor retinoic acid receptor–related orphan receptor (RORα), which is also expressed in common ILC progenitors. To elucidate the developmental pathways of lung ILC2s, we generated RORα lineage tracer mice and performed single-cell RNA sequencing, flow cytometry, and functional analyses. In adult mouse lungs, we found an IL-18Rα+ST2− population different from conventional IL-18Rα−ST2+ ILC2s. The former was GATA-3intTcf7EGFP+Kit+, produced few cytokines, and differentiated into multiple ILC lineages in vivo and in vitro. In neonatal mouse lungs, three ILC populations were identified, namely an ILC progenitor population similar to that in adult lungs and two distinct effector ILC2 subsets that differentially produced type 2 cytokines and amphiregulin. Lung ILC progenitors might actively contribute to ILC-poiesis in neonatal and inflamed adult lungs. In addition, neonatal lung ILC2s include distinct proinflammatory and tissue-repairing subsets.

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“…Thus, the EILP would represent an intermediate developmental stage in which IL‐7Rα is transiently downregulated. Indeed, when the IL7rCre strain was crossed to a ROSA26‐YFP reporter strain and the Tcf7 EGFP reporter, the temporal expression of Tcf7 and IL‐7R amongst IL‐7R + an IL‐7R − cells could be ascertained . Indeed, it was then clear that the IL‐7R − population carried the imprint of previous IL‐7R expression and that the EILP defines a critical step in ILC generation.…”

Section: Innate Lymphoid Cell Subsetsmentioning

confidence: 99%

“…Indeed, it was then clear that the IL‐7R − population carried the imprint of previous IL‐7R expression and that the EILP defines a critical step in ILC generation. Importantly, this work defined the link between the very early progenitor stages of the ALP and ILCP (ILC progenitor), and the EILP, and crucially pinpointed the requirement for differential regulation of receptor expression for this transition that may well have been normally overlooked (Figure ) . IL‐7R expression is therefore highly dynamic and tightly regulated by TCF‐1 resulting in early expression in development, but subsequently downregulated to allow the EILP to give rise to ILCP.…”

Section: Innate Lymphoid Cell Subsetsmentioning

confidence: 99%

Deconstructing deployment of the innate immune lymphocyte army for barrier homeostasis and protection

Almeida

Jacquelot

Belz

2018

Immunological Reviews

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Summary The study of the immune system has shifted from a purely dichotomous separation between the innate and adaptive arms to one that is now highly complex and reshaping our ideas of how steady‐state health is assured. It is now clear that immune cells do not neatly fit into these two streams and immune homeostasis depends on continual dialogue between multiple lineages of the innate (including dendritic cells, innate lymphoid cells, and unconventional lymphocytes) and adaptive (T and B lymphocytes) arms together with a finely tuned synergy between the host and microbes which is essential to ensure immune homeostasis. Innate lymphoid cells are critical players in this new landscape. Here, we discuss recent studies that have elucidated in detail the development of ILC s from their earliest progenitors and examine factors that influence their identification and ability to drive immune homeostasis and long‐term immune protection.

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Development and differentiation of early innate lymphoid progenitors

Abstract: Harly et al. show that early innate lymphoid progenitors (EILPs) are a developmental intermediate between all-lymphoid progenitors (ALPs) and ILC precursors (ILCps) and identify requirements for their generation and further differentiation.

Cited by 88 publications

References 54 publications

Yeats4 drives ILC lineage commitment via activation of Lmo4 transcription

Yeats4 drives ILC lineage commitment via activation of Lmo4 transcription

Single-cell analysis of RORα tracer mouse lung reveals ILC progenitors and effector ILC2 subsets

Deconstructing deployment of the innate immune lymphocyte army for barrier homeostasis and protection

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