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Human IL-25- and IL-33-responsive type 2 innate lymphoid cells are defined by expression of CRTH2 and CD161

Abstract

Innate lymphoid cells (ILCs) are emerging as a family of effectors and regulators of innate immunity and tissue remodeling. Interleukin 22 (IL-22)- and IL-17-producing ILCs, which depend on the transcription factor RORγt, express CD127 (IL-7 receptor α-chain) and the natural killer cell marker CD161. Here we describe another lineage-negative CD127+CD161+ ILC population found in humans that expressed the chemoattractant receptor CRTH2. These cells responded in vitro to IL-2 plus IL-25 and IL-33 by producing IL-13. CRTH2+ ILCs were present in fetal and adult lung and gut. In fetal gut, these cells expressed IL-13 but not IL-17 or IL-22. There was enrichment for CRTH2+ ILCs in nasal polyps of chronic rhinosinusitis, a typical type 2 inflammatory disease. Our data identify a unique type of human ILC that provides an innate source of T helper type 2 (TH2) cytokines.

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Figure 1: Lin lymphocytes in the fetal gut include a CRTH2+CD127+ ILC population.
Figure 2: CRTH2+ fetal gut ILCs express IL13 transcripts ex vivo.
Figure 3: CRTH2+ fetal gut ILCs respond to IL-25 and IL-33 in vitro by producing IL-13.
Figure 4: Analysis of stable cell lines generated from fetal gut CRTH2+ ILCs.
Figure 5: CRTH2+ ILCs are distributed in several fetal and adult tissues and show enrichment in the nasal polyps of patients with chronic rhinosinusitis.
Figure 6: CRTH2+CD127+CCR6+ innate lymphoid cells are present in peripheral blood.
Figure 7: CRTH2+ peripheral blood ILCs respond to IL-25 and IL-33 by producing IL-13 protein.
Figure 8: Stable cell lines can be generated from CRTH2+ peripheral blood ILCs.

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Acknowledgements

We thank B. Hooibrink and J. Cupp and their teams for help with flow cytometry and Luminex assays; W. Ouyang and C. Kaplan for discussions; A. te Velde and C. Ponsioen for help with intestinal tissues; staff of the Bloemenhove clinic in Heemstede, the Netherlands, for fetal tissues; and K. Weijer, A. Voordouw, N. Legrand and B. Olivier for help with processing various tissues.

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J.M.M. designed the study, did experiments, analyzed the data and wrote the manuscript; S.T. designed the study, did experiments, analyzed the data and wrote the manuscript; N.K.C. did experiments and analyzed the data; C.P.P. did experiments, and provided and processed gut tissue; C.M.v.D. and W.J.F. provided inflamed and uninflamed nasal tissue; B.P. provided and processed lung tissue; T.C. designed the study; and H.S. designed the study and wrote the manuscript.

Corresponding author

Correspondence to Hergen Spits.

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The authors declare no competing financial interests.

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Mjösberg, J., Trifari, S., Crellin, N. et al. Human IL-25- and IL-33-responsive type 2 innate lymphoid cells are defined by expression of CRTH2 and CD161. Nat Immunol 12, 1055–1062 (2011). https://doi.org/10.1038/ni.2104

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