Induction of human regulatory innate lymphoid cells from group 2 innate lymphoid cells by retinoic acid

Hideaki Morita, Terufumi Kubo, Beate Rückert, Avinash Ravindran, Michael B. Soyka, Arturo Ottavio Rinaldi, Kazunari Sugita, Marcin Wawrzyniak, Paulina Wawrzyniak, Kenichiro Motomura, Masato Tamari, Keisuke Orimo, Naoko Okada, Ken Arae, Kyoko Saito, Can Altunbulakli, Francesc Castro-Giner, Ge Tan, Avidan Neumann, Katsuko SudoLiam O'Mahony, Kenya Honda, Susumu Nakae, Hirohisa Saito, Jenny Mjösberg, Gunnar Nilsson, Kenji Matsumoto, Mübeccel Akdis, Cezmi A. Akdis

Research output: Contribution to journalArticle

11 Citations (Scopus)

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 T H 2 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.

Original languageEnglish
JournalJournal of Allergy and Clinical Immunology
DOIs
Publication statusPublished - 2019 Jan 1

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Tretinoin
Lymphocytes
Interleukin-10
Nose
Nasal Polyps
Lung
Healthy Volunteers
Epithelial Cells
Inflammation
RNA Sequence Analysis
Pyroglyphidae
Interleukin-13
Chemotactic Factors
T-Lymphocyte Subsets
Regulatory T-Lymphocytes
Helper-Inducer T-Lymphocytes
Dust
Flow Cytometry
Anti-Inflammatory Agents
Down-Regulation

Keywords

  • asthma
  • chronic rhinosinusitis with nasal polyps
  • cytotoxic T lymphocyte–associated protein 4
  • Group 2 innate lymphoid cells
  • IL-33
  • Regulatory innate lymphoid cells
  • retinoic acid

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Induction of human regulatory innate lymphoid cells from group 2 innate lymphoid cells by retinoic acid. / Morita, Hideaki; Kubo, Terufumi; Rückert, Beate; Ravindran, Avinash; Soyka, Michael B.; Rinaldi, Arturo Ottavio; Sugita, Kazunari; Wawrzyniak, Marcin; Wawrzyniak, Paulina; Motomura, Kenichiro; Tamari, Masato; Orimo, Keisuke; Okada, Naoko; Arae, Ken; Saito, Kyoko; Altunbulakli, Can; Castro-Giner, Francesc; Tan, Ge; Neumann, Avidan; Sudo, Katsuko; O'Mahony, Liam; Honda, Kenya; Nakae, Susumu; Saito, Hirohisa; Mjösberg, Jenny; Nilsson, Gunnar; Matsumoto, Kenji; Akdis, Mübeccel; Akdis, Cezmi A.

In: Journal of Allergy and Clinical Immunology, 01.01.2019.

Research output: Contribution to journalArticle

Morita, H, Kubo, T, Rückert, B, Ravindran, A, Soyka, MB, Rinaldi, AO, Sugita, K, Wawrzyniak, M, Wawrzyniak, P, Motomura, K, Tamari, M, Orimo, K, Okada, N, Arae, K, Saito, K, Altunbulakli, C, Castro-Giner, F, Tan, G, Neumann, A, Sudo, K, O'Mahony, L, Honda, K, Nakae, S, Saito, H, Mjösberg, J, Nilsson, G, Matsumoto, K, Akdis, M & Akdis, CA 2019, 'Induction of human regulatory innate lymphoid cells from group 2 innate lymphoid cells by retinoic acid', Journal of Allergy and Clinical Immunology. https://doi.org/10.1016/j.jaci.2018.12.1018
Morita, Hideaki ; Kubo, Terufumi ; Rückert, Beate ; Ravindran, Avinash ; Soyka, Michael B. ; Rinaldi, Arturo Ottavio ; Sugita, Kazunari ; Wawrzyniak, Marcin ; Wawrzyniak, Paulina ; Motomura, Kenichiro ; Tamari, Masato ; Orimo, Keisuke ; Okada, Naoko ; Arae, Ken ; Saito, Kyoko ; Altunbulakli, Can ; Castro-Giner, Francesc ; Tan, Ge ; Neumann, Avidan ; Sudo, Katsuko ; O'Mahony, Liam ; Honda, Kenya ; Nakae, Susumu ; Saito, Hirohisa ; Mjösberg, Jenny ; Nilsson, Gunnar ; Matsumoto, Kenji ; Akdis, Mübeccel ; Akdis, Cezmi A. / Induction of human regulatory innate lymphoid cells from group 2 innate lymphoid cells by retinoic acid. In: Journal of Allergy and Clinical Immunology. 2019.
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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 T H 2 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.",
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T1 - Induction of human regulatory innate lymphoid cells from group 2 innate lymphoid cells by retinoic acid

AU - Morita, Hideaki

AU - Kubo, Terufumi

AU - Rückert, Beate

AU - Ravindran, Avinash

AU - Soyka, Michael B.

AU - Rinaldi, Arturo Ottavio

AU - Sugita, Kazunari

AU - Wawrzyniak, Marcin

AU - Wawrzyniak, Paulina

AU - Motomura, Kenichiro

AU - Tamari, Masato

AU - Orimo, Keisuke

AU - Okada, Naoko

AU - Arae, Ken

AU - Saito, Kyoko

AU - Altunbulakli, Can

AU - Castro-Giner, Francesc

AU - Tan, Ge

AU - Neumann, Avidan

AU - Sudo, Katsuko

AU - O'Mahony, Liam

AU - Honda, Kenya

AU - Nakae, Susumu

AU - Saito, Hirohisa

AU - Mjösberg, Jenny

AU - Nilsson, Gunnar

AU - Matsumoto, Kenji

AU - Akdis, Mübeccel

AU - Akdis, Cezmi A.

PY - 2019/1/1

Y1 - 2019/1/1

N2 - 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 T H 2 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.

AB - 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 T H 2 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.

KW - asthma

KW - chronic rhinosinusitis with nasal polyps

KW - cytotoxic T lymphocyte–associated protein 4

KW - Group 2 innate lymphoid cells

KW - IL-33

KW - Regulatory innate lymphoid cells

KW - retinoic acid

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