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

Rodríguez-Rodríguez, Noé; Clark, Paula A.; Gogoi, Mayuri; Ferreira, Ana Carolina Franco; Kerscher, Bernhard; Crisp, Alastair; Jolin, Helen E.; Murphy, Jane E.; Sivasubramaniam, Meera; Pedro, Luísa; Walker, Jennifer; Heycock, Morgan W D; Shields, Jacqueline D.; Barlow, Jillian; McKenzie, Andrew N. J.

doi:10.1073/pnas.2203454119

Cited by 12 publications

(6 citation statements)

References 83 publications

(252 reference statements)

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“…Consistent with their status as immature precursors, ILCp cells retained heterogenous levels of uncommitted progenitor markers c-Kit, PD-1, and CD44 (Figure S2A-B). Furthermore, mature NK and ILC2 cells were low for c-Kit and CD25 with heterogeneous levels of PD-1 and CD44 (Figure S2A-B), in agreement with previous studies (Rodriguez-Rodriguez et al, 2022). Compared to the wildtype mice, ΔTE mice exhibited significantly elevated frequencies and numbers of ILCp and ILC2 cells in the thymus; they also exhibited a moderate increase in the frequencies of NK cells.…”

Section: Resultssupporting

confidence: 92%

A timed epigenetic switch balances T and ILC lineage proportions in the thymus

Pease,

Chen,

Gerges

et al. 2024

Preprint

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How stem and progenitor cells give rise to multiple cell types in defined numbers and proportions is a central question in developmental biology. Epigenetic switches, acting at single gene loci, can generate extended delays in the activation timing of lineage-specifying genes, and thereby impact lineage decisions and cell type output of progenitors. Here, we analyzed a timed epigenetic switch controlling Bcl11b, a transcription factor that drives T cell lineage commitment, but only after a long multi-day time delay in expression. To investigate roles for this delay in controlling lineage decision making, we analyzed progenitors with a deletion in a distal Bcl11b enhancer, that further extends this delay by ~3 days. Strikingly, delaying Bcl11b activation reduces T cell output but enhances ILC generation in the thymus, and does so by redirecting progenitors to the ILC lineages at the T and ILC developmental branchpoint. Mechanistically, delaying Bcl11b activation promoted ILC redirection by up-regulating a PLZF-dependent ILC transcriptional program in progenitors. Despite up-regulating PLZF, committed ILC progenitors were still capable of later activating Bcl11b, which is also needed for specification of type 2 ILCs. These results show that epigenetic switches, by controlling the activation timing and order of lineage-specifying genes within regulatory networks, can modulate population sizes and proportions of differentiated cell types.

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Section: Resultssupporting

confidence: 92%

A timed epigenetic switch balances T and ILC lineage proportions in the thymus

Pease,

Chen,

Gerges

et al. 2024

Preprint

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“…AceNKPs uniformly express T-bet and are negative for RORα, RORγt, and GATA3 expression and lack ILC2 and ILC3 developmental potential. 35 Furthermore, tissue resident Lin − Sca1 + Mac1 + (LSM) hematopoietic cells of fetal liver origin in the adult liver can differentiate into liver ILC1s. 36 Single cell analysis combined with pseudotime analysis identified Lin − CD122 + CD49a + precursors downstream of LSM cells with liver ILC1 restricted differentiation potential.…”

Section: Ilc De Velopmentmentioning

confidence: 99%

“…These aceNKPs are characterized as Lin − ID2 + IL7Rα + CD25 − α4β7 − NKG2A/C/E + Bcl11b − cells and can give rise to ILC1/NK cells. AceNKPs uniformly express T‐bet and are negative for RORα, RORγt, and GATA3 expression and lack ILC2 and ILC3 developmental potential 35 …”

Section: Ilc Developmentmentioning

confidence: 99%

Group 1 ILCs: Heterogeneity, plasticity, and transcriptional regulation

Sudan,

Gilfillan,

Colonna

2024

Immunological Reviews

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SummaryGroup 1 innate lymphoid cells (ILCs), comprising ILC1s and natural killer cells (NK cells), belong to a large family of developmentally related innate lymphoid cells that lack rearranged antigen‐specific receptors. NK cells and ILC1s both require the transcription factor T‐bet for lineage commitment but additionally rely on Eomes and Hobit, respectively, for their development and effector maturation programs. Both ILC1s and NK cells are essential for rapid responses against infections and mediate cancer immunity through production of effector cytokines and cytotoxicity mediators. ILC1s are enriched in tissues and hence generally considered tissue resident cells whereas NK cells are often considered circulatory. Despite being deemed different cell types, ILC1s and NK cells share many common features both phenotypically and functionally. Recent studies employing single cell RNA sequencing (scRNA‐seq) technology have exposed previously unappreciated heterogeneity in group 1 ILCs and further broaden our understanding of these cells. Findings from these studies imply that ILC1s in different tissues and organs share a common signature but exhibit some unique characteristics, possibly stemming from tissue imprinting. Also, data from recent fate mapping studies employing Hobit, RORγt, and polychromic reporter mice have greatly advanced our understanding of the developmental and effector maturation programs of these cells. In this review, we aim to outline the fundamental traits of mouse group 1 ILCs and explore recent discoveries related to their developmental programs, phenotypic heterogeneity, plasticity, and transcriptional regulation.

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“…In contrast, it has been proposed that ILC1s may express one of T-bet or in rarer cases Eomes, but not both [ 15 ]. Recently, a common group 1 ILC progenitor was identified, called aceNKP, which differentiates into a spectrum of group 1 ILCs, indicating that this group is formed of a continuum, rather than discrete populations of cells [ 16 ]. While unlike NK, B and T cells, ILCs are mainly tissue-resident cells [ 17 ], some migration does occur with ILC1s being the main migratory ILC subset [ 18 ].…”

Section: Introductionmentioning

confidence: 99%

“…Some studies have suggested that functionally, the maturation of NK cells requires the sequential activation of Eomes then T-bet [14]. In contrast, it has been proposed that ILC1s may express one of T-bet or in rarer cases Eomes, but not both [15]. Recently, a common group 1 ILC progenitor was identified, called aceNKP, which differentiates into a spectrum of group 1 ILCs, indicating that this group is formed of a continuum, rather than discrete populations of cells [16].…”

Section: Introductionmentioning

confidence: 99%

Emerging roles of type 1 innate lymphoid cells in tumour pathogenesis and cancer immunotherapy

Verner,

Arbuthnott,

Ramachandran

et al. 2024

Exploration of Targeted Anti-Tumor Therapy

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Innate lymphoid cells (ILCs) are the most recently discovered class of innate immune cells found to have prominent roles in various human immune-related pathologies such as infection and autoimmune diseases. However, their role in cancer was largely unclear until recently, where several emerging studies over the past few years unanimously demonstrate ILCs to be critical players in tumour immunity. Being the innate counterpart of T cells, ILCs are potent cytokine producers through which they orchestrate the overall immune response upstream of adaptive immunity thereby modulating T cell function. Out of the major ILC subsets, ILC1s have gained significant traction as potential immunotherapeutic candidates due to their central involvement with the anti-tumour type 1 immune response. ILC1s are potent producers of the well-established anti-tumour cytokine interferon γ (IFNγ), and exert direct cytotoxicity against cancer cells in response to the cytokine interleukin-15 (IL-15). However, in advanced diseases, ILC1s are found to demonstrate an exhausted phenotype in the tumour microenvironment (TME) with impaired effector functions, characterised by decreased responsiveness to cytokines and reduced IFNγ production. Tumour cells produce immunomodulatory cytokines such as transforming growth factor β (TGFβ) and IL-23, and through these suppress ILC1 anti-tumour actfivities and converts ILC1s to pro-tumoural ILC3s respectively, resulting in disease progression. This review provides a comprehensive overview of ILC1s in tumour immunity, and discusses the exciting prospects of harnessing ILC1s for cancer immunotherapy, either alone or in combination with cytokine-based treatment. The exciting prospects of targeting the upstream innate immune system through ILC1s may surmount the limitations associated with adaptive immune T cell-based strategies used in the clinic currently, and overcome cancer immunotherapeutic resistance.

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

Cited by 12 publications

References 83 publications

A timed epigenetic switch balances T and ILC lineage proportions in the thymus

A timed epigenetic switch balances T and ILC lineage proportions in the thymus

Group 1 ILCs: Heterogeneity, plasticity, and transcriptional regulation

Emerging roles of type 1 innate lymphoid cells in tumour pathogenesis and cancer immunotherapy

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