Plasticity of innate lymphoid cell subsets

Bal, Suzanne M.; Golebski, Korneliusz; Spits, Hergen

doi:10.1038/s41577-020-0282-9

Cited by 238 publications

(289 citation statements)

References 147 publications

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“…ILC3s depend on retinoic acid receptor-related orphan receptor-ct for their development and function and comprise subsets that can be distinguished by the expression of the natural cytotoxicity receptors NK46 and NKp44. The major cytokine produced by ILC3s is IL22, and a population of ILC3s also produces IL-17 [7]. The view of cytokine profile indicates that ILCs are involved in the pathophysiology of IBD [8].…”

Section: The Pathophysiology and Treatment Of Ibd From The Perspectivmentioning

confidence: 99%

Treatment of inflammatory bowel disease from the immunological perspective

Nakase

2020

Immunological Medicine

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Since 1950, the number of patients with inflammatory bowel disease (IBD) in Japan has been increasing. Recent research data indicate that the pathophysiology of IBD involves abnormalities in disease susceptibility genes, environmental factors and intestinal bacteria. The elucidation of the mechanism of IBD has facilitated therapeutic development based on basic research data. In particular, the emergence of biologics has brought about a paradigm shift in the treatment of IBD. However, there are still IBD patients who are refractory to these biologics. IBD pathophysiology is extremely complex. Therefore, to address these clinical issues, further clinical and basic data are required. The bottom line of IBD drug therapy is still to use the most of recent treatments. Therefore, the physicians should be familiar with the modes of action (MOA) of the available drugs.

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Section: The Pathophysiology and Treatment Of Ibd From The Perspectivmentioning

confidence: 99%

Treatment of inflammatory bowel disease from the immunological perspective

Nakase

2020

Immunological Medicine

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“…Speculation about the impact of TGFβ1 in the context of the gastro-intestinal immune system is a complex task, as the microbiome, the enteric nervous system, and other immune cells differentially respond to this pleiotropic cytokine. For instance, while TGFβ1 is a master regulator of fibrosis in fibroblasts 31 , it is anti-inflammatory in the adaptive immune system 32 , and can regulate plasticity between the ILC subsets 33 . We observed expression of TGFβ1 in tandem with IFN , suggesting that these cytokines may act in concert, and highlighting the importance of our dataset being derived from co-cultures with ILC1, not recombinant cytokines.…”

Section: Discussionmentioning

confidence: 99%

ILC1-derived TGFβ1 drives intestinal remodelling

Jowett

Norman

et al. 2020

Preprint

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Organoids can shed light on the dynamic interplay between complex tissues and rare cell types within a controlled microenvironment. Here, we developed gut organoid co-cultures with type-1 innate lymphoid cells (ILC1) to dissect the impact of their accumulation in inflamed intestines.We demonstrate for the first time that murine and human ILC1 secrete TGFβ1, driving expansion of CD44v6 + epithelial crypts. ILC1 additionally express MMP9 and drive gene signatures indicative of extracellular matrix remodelling. We therefore encapsulated human epithelial-mesenchymal intestinal organoids in MMP-sensitive, synthetic hydrogels designed to form efficient networks at low polymer concentrations. Harnessing this defined system, we demonstrate that ILC1 drive matrix softening and stiffening, which we suggest occurs through balanced matrix degradation and deposition. Our platform enabled us to elucidate previously undescribed interactions between ILC1 and their microenvironment, which suggest that they may exacerbate fibrosis and tumour growth when enriched in inflamed patient tissues. MainIntestinal epithelial cells (IEC) 1 interact with innate lymphoid cells (ILC) 2 to form a dynamic barrier between organisms and their environment. Together, they are capable of rapidly responding to danger and damage in an antigen non-specific manner. For instance, type-3 ILC3 secrete Interleukin-22 (IL-22, Il22 ) in response to extracellular pathogens, which promotes anti-microbial peptide secretion and proliferation of Lgr5 + CD44 + intestinal stem cells 3 .Conversely, type-1 ILC express Interferon-gamma (IFNγ, Ifng ) in response to intracellular pathogens, and are comprised of circulating natural killer (NK) cells and tissue resident helper-like ILC1 (ILC1), which are considered less cytotoxic than their NK-cell counterparts 4 .Notably, ILC1 accumulate in the inflamed intestines of Inflammatory Bowel Disease (IBD) patients 5 , however the nature of their subset-specific interactions with the epithelium has remained elusive. Understanding the impact of ILC1 enrichment could offer novel avenues for treating this complex disease, which is a pressing issue as only a third of patients respond to gold standard TNFα-blocking biologics 6 .Teasing apart the role of rare cell populations in multifactorial diseases is challenging, and redundant cytokine signalling pathways in vivo can obscure ILC-specific phenotypes. Thus, to explore the impact of ILC1 on IEC we developed a reductionist co-culture system with murine small intestine organoids (SIO) 7 . We unexpectedly found that ILC1-derived TGFβ1 induces p38γ activity to drive epithelial Cd44v6 expression and SIO proliferation. Pathway analysis of co-culture transcriptomes also predicted ILC1-driven matrisome remodelling, so we developed highly defined PEG-based hydrogels to quantitatively characterize the impact of ILC1 on matrix remodelling in a human iPSC-derived organoid model (HIO) 8 . We not only confirmed that IBD patient-derived ILC1 express TGFB1 and upregulate CD44v6, but also that they p...

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“…Whilst ILCs are derived from lymphoid progenitors, they do not express antigen-specific B-cell or T-cell receptors. Four major groups of ILCs have been defined: natural killer (NK) cells, group 1 ILCs (ILC1s), group 2 ILCs (ILC2s) and group 3 ILCs (ILC3s) [61]. NK cells have cytotoxic potential against tumour cells and can target cells that lack MHCI expression and express the correct balance of activating and inhibitory ligands to NK cell receptors.…”

Section: Innate Lymphoid Cellsmentioning

confidence: 99%

“…NK cells have cytotoxic potential against tumour cells and can target cells that lack MHCI expression and express the correct balance of activating and inhibitory ligands to NK cell receptors. ILC1s, ILC2s and ILC3s possess properties of Th1, Th2 and Th17 cells, respectively, and therefore help direct the innate and adaptive immune response [61].…”

Section: Innate Lymphoid Cellsmentioning

confidence: 99%

“…In colorectal and lung tumours, NK cells were the predominant ILC; however, the other subtypes were present at different abundances [67]. ILC1s are typically activated by cytokines such as IL-12, IL-15, IL-18 and TGF-b, and their function varies depending on the cytokines present [61]. In mice, IL-15-rich environments cause an expansion of tissue-resident ILC1-like cells, which can limit tumour growth independent of NK cells [68].…”

Section: Innate Lymphoid Cellsmentioning

confidence: 99%

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Autophagy, the innate immune response and cancer

Gerada

Ryan

2020

Molecular Oncology

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Both autophagy, a cellular recycling process, and the innate immune response can have different effects on tumour formation at different stages. Interestingly, autophagy and the innate immune response interact during tumorigenesis to have both tumour‐promoting and tumour‐inhibiting affects. By dissecting the interaction between autophagy and the innate immune response during tumour formation, novel therapeutic strategies may be identified.

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Plasticity of innate lymphoid cell subsets

Cited by 238 publications

References 147 publications

Treatment of inflammatory bowel disease from the immunological perspective

Treatment of inflammatory bowel disease from the immunological perspective

ILC1-derived TGFβ1 drives intestinal remodelling

Autophagy, the innate immune response and cancer

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