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

Publication date: Available online 22 January 2019

Source: Journal of Allergy and Clinical Immunology

Author(s): 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 Sudo

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 the regulation of ILC2 activation has received significant attention. Although ILCs are divided into three major subsets that mirror helper effector T-cell subsets, counterpart subsets of regulatory T (Treg) cells have not been well characterized.

Objective

We sought to determine the factors that induce regulatory ILCs (ILCregs).

Methods

IL-10⁺ ILCregs induced from ILC2s by retinoic acid (RA) were analyzed using RNA-sequencing and flow cytometry. ILCregs were evaluated in human nasal tissues from healthy individuals and patients with chronic rhinosinusitis with nasal polyp (CRSwNP), and in lung tissues from house dust mite (HDM)- or saline-treated mice.

Results

RA induced IL-10 secretion by human ILC2s, but not type-2 cytokines. IL-10⁺ ILCregs, converted from ILC2s by RA stimulation, expressed a Treg-like signature with the expression of IL-10, CTLA-4 and CD25, with down regulated effector type 2-related markers such as CRTH-2 and ST2, and suppressed activation of CD4⁺ T cells and ILC2s. ILCregs were rarely detected in human nasal tissue from healthy individuals or lung tissues from saline-treated mice, but were increased in nasal tissues from patients with CRSwNP and in lung tissues from HDM-treated mice. Enzymes for RA synthesis were up-regulated 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.

Graphical abstract

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