Prostaglandin D2 activates group 2 innate lymphoid cells through chemoattractant receptor-homologous molecule expressed on TH2 cells

doi:10.1016/j.jaci.2013.10.056

Journal of Allergy and Clinical Immunology

Volume 133, Issue 4, April 2014, Pages 1184-1194.e7

https://doi.org/10.1016/j.jaci.2013.10.056 Get rights and content

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Background

Activation of the group 2 innate lymphoid cell (ILC2) population leads to production of the classical type 2 cytokines, thus promoting type 2 immunity. Chemoattractant receptor-homologous molecule expressed on T_H2 cells (CRTH2), a receptor for prostaglandin D₂ (PGD₂), is expressed by human ILC2s. However, the function of CRTH2 in these cells is unclear.

Objectives

We sought to determine the role of PGD₂ and CRTH2 in human ILC2s and compare it with that of the established ILC2 activators IL-25 and IL-33.

Methods

The effects of PGD₂, IL-25, and IL-33 on the cell migration, cytokine production, gene regulation, and receptor expression of ILC2s were measured with chemotaxis, ELISA, Luminex, flow cytometry, quantitative RT-PCR, and QuantiGene assays. The effects of PGD₂ under physiologic conditions were evaluated by using the supernatant from activated mast cells.

Results

PGD₂ binding to CRTH2 induced ILC2 migration and production of type 2 cytokines and many other cytokines. ILC2 activation through CRTH2 also upregulated the expression of IL-33 and IL-25 receptor subunits (ST2 and IL-17RA). The effects of PGD₂ on ILC2s could be mimicked by the supernatant from activated human mast cells and inhibited by a CRTH2 antagonist.

Conclusions

PGD₂ is an important and potent activator of ILC2s through CRTH2 mediating strong proallergic inflammatory responses. Through IgE-mediated mast cell degranulation, these innate cells can also contribute to adaptive type 2 immunity; thus CRTH2 bridges the innate and adaptive pathways in human ILC2s.

Key words

Group 2 innate lymphoid cell

PGD₂

chemoattractant receptor-homologous molecule expressed on T_H2 cells

IL-25

IL-33

innate type 2 immunity

adaptive type 2 immunity

Abbreviations used

CRTH2

Chemoattractant receptor-homologous molecule expressed on T_H2 cells

CSF-1

Macrophage colony-stimulating factor

cysLT

Cysteinyl leukotriene

CysLT₁

Cysteinyl leukotriene receptor 1

EC₅₀

Median effective concentration

ILC

Innate lymphoid cell

ILC2

Group 2 innate lymphoid cell

PGD₂

Prostaglandin D₂

Cited by (0)

: Supported by the Wellcome Trust (to P.K.), the Medical Research Council (to G.O.), NIHR Biomedical Research Centre Programme (to L.X., G.O., and M.S.), Oxford Martin School (to P.K.), the British Medical Association (James Trust; to G.O., P.K., and L.X.), Oxfordshire Health Services Research Committee Research Grant (to L.X.), and the National Institutes of Health (to P.K. and L.X.). P.K. is an NIHR Senior Investigator.

: Disclosure of potential conflict of interest: J. M. Mjösberg has received research support from the Swedish Research Council. A. N. J. McKenzie has received research support from, has patents (planned, pending, or issued) from, and has royalties from Janssen. H. Spits has received research support from the ERC as an advanced grant; is employed by the Academic Medical Center of the University of Amsterdam; and is employed by, has patents planned, pending, or issued from, has stock/stock options in, and is a founder of AIMM therapeutics. P. Klenerman has received research support from The Wellcome Trust, the NIH, and the NIHR Biomedical Research Centre. G. Ogg has received research support from the Medical Research Council, the Biomedical Research Centre, the British Medical Association, and Janssen Pharmaceuticals and has received consultancy fees from Novartis and Lilly. The rest of the authors declare that they have no relevant conflicts of interest.

^∗: These authors contributed equally to this work.

^‡: These authors contributed equally to this work as joint senior authors.