Induction of human regulatory innate lymphoid cells from group 2 innate lymphoid cells by retinoic acid - 06/06/19
, Terufumi Kubo, MD, PhD a, b, Beate Rückert, Sci Tec a, Avinash Ravindran, Msc d, Michael B. Soyka, MD e, Arturo Ottavio Rinaldi, Msc a, Kazunari Sugita, MD, PhD a, b, Marcin Wawrzyniak, PhD a, b, Paulina Wawrzyniak, PhD a, b, Kenichiro Motomura, MD, PhD c, Masato Tamari, MD, PhD c, Keisuke Orimo, MD c, Naoko Okada, PhD c, Ken Arae, PhD c, f, Kyoko Saito, MD c, Can Altunbulakli, PhD a, b, Francesc Castro-Giner, PhD a, g, Ge Tan, PhD a, g, Avidan Neumann, PhD a, Katsuko Sudo, PhD h, Liam O'Mahony, PhD a, i, Kenya Honda, MD, PhD j, k, Susumu Nakae, PhD l, m, Hirohisa Saito, MD, PhD c, Jenny Mjösberg, PhD n, Gunnar Nilsson, PhD d, Kenji Matsumoto, MD, PhD c, Mübeccel Akdis, MD, PhD a, b, Cezmi A. Akdis, MD a, b, ⁎ Abstract |
Background |
Group 2 innate lymphoid cells (ILC2s) play critical roles in induction and exacerbation of allergic airway inflammation. Thus clarification of the mechanisms that underlie regulation of ILC2 activation has received significant attention. Although innate lymphoid cells are divided into 3 major subsets that mirror helper effector T-cell subsets, counterpart subsets of regulatory T cells have not been well characterized.
Objective |
We sought to determine the factors that induce regulatory innate lymphoid cells (ILCregs).
Methods |
IL-10+ ILCregs induced from ILC2s by using retinoic acid (RA) were analyzed with RNA-sequencing and flow cytometry. ILCregs were evaluated in human nasal tissue from healthy subjects and patients with chronic rhinosinusitis with nasal polyps and lung tissue from house dust mite– or saline-treated mice.
Results |
RA induced IL-10 secretion by human ILC2s but not type 2 cytokines. IL-10+ ILCregs, which were converted from ILC2s by means of RA stimulation, expressed a regulatory T cell–like signature with expression of IL-10, cytotoxic T lymphocyte–associated protein 4, and CD25, with downregulated effector type 2–related markers, such as chemoattractant receptor–homologous molecule on TH2 cells and ST2, and suppressed activation of CD4+ T cells and ILC2s. ILCregs were rarely detected in human nasal tissue from healthy subjects or lung tissue from saline-treated mice, but numbers were increased in nasal tissue from patients with chronic rhinosinusitis with nasal polyps and in lung tissue from house dust mite–treated mice. Enzymes for RA synthesis were upregulated in airway epithelial cells during type 2 inflammation in vivo and by IL-13 in vitro.
Conclusion |
We have identified a unique immune regulatory and anti-inflammatory pathway by which RA converts ILC2s to ILCregs. Interactions between airway epithelial cells and ILC2s play an important roles in the generation of ILCregs.
Le texte complet de cet article est disponible en PDF.Graphical abstract |
Key words : Regulatory innate lymphoid cells, Group 2 innate lymphoid cells, retinoic acid, IL-33, asthma, chronic rhinosinusitis with nasal polyps, cytotoxic T lymphocyte–associated protein 4
Abbreviation used : ALI, BALF, CFSE, CRSwNP, CRTH2, CTLA-4, DAPI, Foxp3, HDM, Id3, ILC, ILC1, ILC2, ILC210, ILC3, ILCreg, IL-10R, KLRG1, MMP-7, PE, PMA, RA, RALDH, RAR, RNA-seq, TCR, Treg
Plan
| Supported by Swiss National Science Foundation grants 310030_156823 and 320030_140772 (to C.A.), Grants-in-Aid for Young Scientists (B; to H.M.), MSD Life Science Foundation, Public Interest Incorporated Foundation (to H.M.), a Grant of National Center for Child Health and Development (#29-2; to H.M.), and Precursory Research for Embryonic Science and Technology,Japan Science and Technology Agency (to S.N.), Heart and Lung Foundation, Swedish Research Council, and the ChAMP (Centre for Allergy Research Highlights Asthma Markers of Phenotype) consortium funded by the Swedish Foundation for Strategic Research, the Karolinska Institutet, and AstraZeneca & Science for Life Laboratory Joint Research Collaboration (to J.M. and G.N.). |
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| Disclosure of potential conflict of interest: C. A. Akdis has consultant arrangements with Actellion, Aventis, Allergopharma and Circacia and has received grants from Novartis. H. Saito has received personal fees from Shiseido and AstraZeneca. K. Matsumoto has received speakers' bureaus from Merck Sharp and Dohme, AstraZeneca, Kyorin Pharmaceutical, Maruho, and Chugai Pharmaceutical. The rest of the authors declare that they have no relevant conflicts of interest. |
Vol 143 - N° 6
P. 2190 - juin 2019 Retour au numéro
Article précédent
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