Prostaglandin D₂ activates group 2 innate lymphoid cells through chemoattractant receptor-homologous molecule expressed on T_H2 cells

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• 作者：Luzheng Xue ; PhD^a ; ^&lowast ; ; ^{luzheng.xue@ndm.ox.ac.uk" class="auth_mail} ; Maryam Salimi ; MD^a ; ^b ; ^&lowast ; ; Isabel Panse ; BTA^a ; Jenny M. Mjö ; sberg ; PhD^c ; Andrew N.J. McKenzie ; PhD^d ; Hergen Spits ; PhD^e ; Paul Klenerman ; F Med Sci^a ; ^f ; ^&Dagger ; ; ^{paul.klenerman@medawar.ox.ac.uk" class="auth_mail} ; Graham Ogg ; DPhil ; FRCP^a ; ^b ; ^&Dagger ;
• 关键词：Group 2 innate lymphoid cell ; PGD2 ; chemoattractant receptor-homologous molecule expressed on TH2 cells ; IL-25 ; IL-33 ; innate type 2 immunity ; adaptive type 2 immunity
• 刊名：Journal of Allergy and Clinical Immunology
• 出版年：April, 2014
• 年：2014
• 卷：133
• 期：4
• 页码：1184-1194.e7
• 全文大小：2610 K

文摘

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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.