ILC2s regulate adaptive Th2 cell functions via PD-L1 checkpoint control

Schwartz, Christian; Khan, Adnan; Floudas, Achilleas; Saunders, Sean P.; Hams, Emily; Rodewald, Hans Reimer; McKenzie, Andrew N. J.; Fallon, Padraic G.

doi:10.1084/jem.20170051

Cited by 116 publications

(116 citation statements)

References 76 publications

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“…Future studies using mice deficient in PD‐L1 or PD‐L2 could shed light on whether the ligands for PD‐1 can affect ILC2 functions. Indeed, PD‐L1 expression on ILC2 has recently been shown to be important in maintaining/inducing Th2 responses through PD‐1 on Th2 cells …”

Section: Discussionmentioning

confidence: 99%

PD‐1 expression affects cytokine production by ILC2 and is influenced by peroxisome proliferator‐activated receptor‐γ

Batyrova

Luwaert

Maravelia

et al. 2019

Immunity Inflam & Disease

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Introduction Innate lymphoid cells (ILCs) can provide early cytokine help against a variety of pathogens in the lungs and gastrointestinal tract. Type 2 ILC (ILC2) are comparable to T helper 2 cells found in the adaptive immune system, which secrete cytokines such as interleukin 5 (IL‐5) and IL‐13 and have been found to play roles in host defense against helminth infections and in allergic responses. Recent studies have identified that programmed cell death protein 1 (PD‐1) and peroxisome proliferator activated receptor‐γ (PPAR‐γ) are highly expressed by ILC2. We examined whether PD‐1 plays a role in ILC2 function and whether there was any connection between PD‐1 and PPAR‐γ Methods To ensure that only innate immune cells were present, ILC2 cells were examined from RAG1−/− and PD‐1−/−xRAG1−/− mice under steady‐state or following inoculation with IL‐33. We also tested ILC2 generated from bone marrow of RAG1−/− and PD‐1−/−xRAG1−/− mice for their production of cytokines. These in vitro‐derived ILC2 were also exposed to agonist and antagonist of PPAR‐γ. Results We found that ILC2 from PD‐1−/−xRAG1−/− mice had reduced frequencies of IL‐5 and IL‐13 producing cells both in vitro upon IL‐33 stimulation and in vivo following intraperitoneal administration of IL‐33 when compared with ILC2 from RAG1−/− mice. However, by adding IL‐2, IL‐25, and thymic stromal lymphopoietin to the in vitro cultures, the frequency of IL‐5 and IL‐13 expressing ILC2 from PD‐1−/−xRAG1−/− mice became similar to the frequency observed for ILC2 from RAG1−/− mice. In addition, PPAR‐γ agonists and antagonists were found to increase and decrease PD‐1 expression on ILC2 respectively. Conclusions These findings illustrate that chronic loss of PD‐1 plays a role in ILC2 function and PD‐1 expression can be modulated by PPAR‐γ.

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Section: Discussionmentioning

confidence: 99%

PD‐1 expression affects cytokine production by ILC2 and is influenced by peroxisome proliferator‐activated receptor‐γ

Batyrova

Luwaert

Maravelia

et al. 2019

Immunity Inflam & Disease

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“…RAG2 −/− γ c −/− mice that received PD1‐deficient ILC2s had elevated frequencies of cytokine‐producing KLRG1 + ILC2s and were better in clearing worms than mice that received WT ILC2s . ILC2s also express elevated levels of the PD‐1 ligand PD‐L1 after administration of IL‐33 both in vitro and in vivo . Mice lacking PD‐L1 were less efficient in clearing worms than WT mice, although ILC2 proliferation and cytokine production were unchanged .…”

Section: Inhibition Of Ilc2s By Extrinsic Signalsmentioning

confidence: 99%

“…ILC2s also express elevated levels of the PD‐1 ligand PD‐L1 after administration of IL‐33 both in vitro and in vivo . Mice lacking PD‐L1 were less efficient in clearing worms than WT mice, although ILC2 proliferation and cytokine production were unchanged . Instead, ILC2s regulated the T‐cell response via PD‐L1 expression.…”

Section: Inhibition Of Ilc2s By Extrinsic Signalsmentioning

confidence: 99%

“…Instead, ILC2s regulated the T‐cell response via PD‐L1 expression. Binding of PD‐L1 to PD‐1 expressed on T cells induced expression of GATA3 and IL‐13 in Th2 cells, which facilitated worm clearance in a mouse model of helminth infection …”

Section: Inhibition Of Ilc2s By Extrinsic Signalsmentioning

confidence: 99%

“…Murine ILC2s express transcripts for the type 2 cytokines IL‐4, IL‐5, and IL‐13 . However, while activated ILC2s generally produce large amounts of IL‐5 and IL‐13, IL‐4 is typically barely detectable on a protein level, except in specific inflammatory settings or disease models . ILC2s in airway inflammation induced by OVA or house dust mite produce IL‐5 and IL‐13, and less IL‐4, and during helminth infection, ILC2s produce IL‐13 but not IL‐4 .…”

Section: Effector Function Of Ilc2smentioning

confidence: 99%

See 2 more Smart Citations

Type 2 innate lymphoid cells in the induction and resolution of tissue inflammation

Wallrapp

Riesenfeld

Burkett

et al. 2018

Immunological Reviews

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Summary Type 2 immunity against pathogens is tightly regulated to ensure appropriate inflammatory responses that clear infection and prevent excessive tissue damage. Recent research has shown that type 2 innate lymphoid cells (ILC2s) contribute to steady‐state tissue integrity and exert tissue‐specific functions. However, upon exposure to inflammatory stimuli, they also initiate and amplify type 2 inflammation by inducing mucus production, eosinophilia, and Th2 differentiation. In this review, we discuss the regulation of ILC2 activation by transcription factors and metabolic pathways, as well as by extrinsic signals such as cytokines, lipid mediators, hormones, and neuropeptides. We also review recent discoveries about ILC2 plasticity and heterogeneity in different tissues, as revealed partly through single‐cell RNA sequencing of transcriptional responses to various stimuli. Understanding the tissue‐specific pathways that regulate ILC2 diversity and function is a critical step in the development of potential therapies for allergic diseases.

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Interleukin (IL)‐33: an orchestrator of immunity from host defence to tissue homeostasis

2020

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Interleukin (IL)-33, a member of the IL-1 superfamily, functions as an alarm signal, which is released upon cell injury or tissue damage to alert the immune system. It has emerged as a chief orchestrator in immunity and has a broad pleiotropic action that influences differentiation, maintenance and function of various immune cell types via the ST2 receptor. Although it has been strongly associated with immunopathology, critically, IL-33 is involved in host defence, tissue repair and homeostasis. In this review, we provide an overview of the signalling pathway of IL-33 and highlight its regulatory functions in immune cells. Furthermore, we attempt a broader discussion of the emerging functions of IL-33 in host defence, tissue repair, metabolism, inflammatory disease and cancer, suggesting potential avenues to manoeuvre IL-33/ST2 signalling as treatment options.

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ILC2s regulate adaptive Th2 cell functions via PD-L1 checkpoint control

Cited by 116 publications

References 76 publications

PD‐1 expression affects cytokine production by ILC2 and is influenced by peroxisome proliferator‐activated receptor‐γ

PD‐1 expression affects cytokine production by ILC2 and is influenced by peroxisome proliferator‐activated receptor‐γ

Type 2 innate lymphoid cells in the induction and resolution of tissue inflammation

Interleukin (IL)‐33: an orchestrator of immunity from host defence to tissue homeostasis

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