PD-1 regulates KLRG1+ group 2 innate lymphoid cells

Taylor, Samuel; Huang, Yao‐Zeng; Mallett, Grace; Stathopoulou, Chaido; Felizardo, Tania C.; Sun, Ming-an; Martin, Evelyn L.; Zhu, Nathaniel; Woodward, Emma; Elias, Martina S.; Scott, Jonathan; Reynolds, Nick J.; Paul, William E.; Fowler, Daniel H.; Amarnath, Shoba

doi:10.1084/jem.20161653

Cited by 167 publications

(182 citation statements)

References 62 publications

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“…Our results are slightly at odds with a previous publication that demonstrated that KLRG1 + PD‐1 + ILC2 produce more Th2 cytokines following both IN delivery of IL‐33 and during infection with the worm Nippostrongylus brasiliensis . In our study, we found that there were no differences between ILC2 from RAG1 −/− and PD‐1xRAG1 −/− mice in their expression of KLRG1.…”

Section: Discussioncontrasting

confidence: 99%

“…In the present study, we have demonstrated that chronic loss of PD‐1 expression on ILC2 might have a role in maintaining cytokine production in these cells and expression of receptors associated with ILC2 function. Since ILC2 can express PD‐1 and with current anti‐PD‐1 or anti‐PD‐L1 therapies for the treatment of cancers, it would be interesting to examine whether some of the functions associated with ILC2 are also affected in these patients. For example, skewing of Th2 cytokines might have both beneficial as well as detrimental effects on tumor therapies …”

Section: Discussionmentioning

confidence: 99%

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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: Discussioncontrasting

confidence: 99%

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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“…Lipoxin A4, PGI 2 and maresin 1 are eicosanoids that have been suggested as pro-resolving mediators in severe asthma with direct suppressive effects on IL-13 production by ILC2s [44,55,56]. Similar to T cells, PD-1 signaling in ILC2s limits their expansion and cytokine production by reducing STAT5 activity [57]. …”

Section: Regulation Of Ilc2 Activation In Barrier Tissuesmentioning

confidence: 99%

All along the watchtower: group 2 innate lymphoid cells in allergic responses

Dahlgren

Molofsky

2018

Current Opinion in Immunology

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Group 2 innate lymphoid cells (ILC2) are a subset of innate lymphocytes that responds to local, tissue-derived signals and initiates allergic immune responses. ILC2 activation promotes the recruitment of eosinophils, polarization of alternatively activated macrophages, and tissue-remodeling, processes associated with the 'weep and sweep' response to helminthic worm colonization and infection. ILC2s also coordinate both physiologic and pathologic type 2 allergic immune responses, including promoting normal tissue development and remodeling and driving allergic pathology such as atopic dermatitis and allergic asthma. In this review we summarize recent advances in ILC2 biology, particularly focusing on how local cells and signals coordinately regulate ILC2s, how this may influence physiologic processes, and how ILC2 cooperate with adaptive T helper type 2 cells to drive pathologic allergic inflammation.

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“…In mice, programmed death 1 (PD‐1) is expressed on ILC2s and ILC3s and upregulated especially on ILC2s during inflammation, whereas in humans PD‐1 is predominantly found on ILC2s . Treatment of RAG1 −/− mice with PD‐1 antibody led to the loss of almost all PD‐1 hi ILC2s and resulted in a greatly diminished type 2 immunopathology in response to papain challenge .…”

Section: Inhibition Of Ilc2s By Extrinsic Signalsmentioning

confidence: 99%

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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PD-1 regulates KLRG1+ group 2 innate lymphoid cells

Abstract: Taylor et al. show that PD1 negatively regulates KLRG1+ ILC-2s by attenuating STAT5 activation. Blocking PD1 signaling significantly enhances the protective function of ILC-2s in helminthic infection.

Cited by 167 publications

References 62 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

All along the watchtower: group 2 innate lymphoid cells in allergic responses

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

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