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J Allergy Clin Immunol. 2017 May;139(5):1468-1477.e2. doi: 10.1016/j.jaci.2016.08.034. Epub 2016 Oct 4.

Type 2 innate lymphoid cell suppression by regulatory T cells attenuates airway hyperreactivity and requires inducible T-cell costimulator-inducible T-cell costimulator ligand interaction.

Author information

1
Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, Calif.
2
Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, Calif; Janssen Research and Development, San Diego, Calif.
3
Janssen Research and Development, San Diego, Calif.
4
Department of Medical Oncology, Dana-Farber Cancer Institute, Department of Medicine, Harvard Medical School, Boston, Mass.
5
Department of Microbiology and Immunology, Harvard Medical School, Boston, Mass.
6
Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, Calif. Electronic address: akbari@usc.edu.

Abstract

BACKGROUND:

Atopic diseases, including asthma, exacerbate type 2 immune responses and involve a number of immune cell types, including regulatory T (Treg) cells and the emerging type 2 innate lymphoid cells (ILC2s). Although ILC2s are potent producers of type 2 cytokines, the regulation of ILC2 activation and function is not well understood.

OBJECTIVE:

In the present study, for the first time, we evaluate how Treg cells interact with pulmonary ILC2s and control their function.

METHODS:

ILC2s and Treg cells were evaluated by using in vitro suppression assays, cell-contact assays, and gene expression panels. Also, human ILC2s and Treg cells were adoptively transferred into NOD SCID γC-deficient mice, which were given isotype or anti-inducible T-cell costimulator ligand (ICOSL) antibodies and then challenged with IL-33 and assessed for airway hyperreactivity.

RESULTS:

We show that induced Treg cells, but not natural Treg cells, effectively suppress the production of the ILC2-driven proinflammatory cytokines IL-5 and IL-13 both in vitro and in vivo. Mechanistically, our data reveal the necessity of inducible T-cell costimulator (ICOS)-ICOS ligand cell contact for Treg cell-mediated ILC2 suppression alongside the suppressive cytokines TGF-β and IL-10. Using a translational approach, we then demonstrate that human induced Treg cells suppress syngeneic human ILC2s through ICOSL to control airway inflammation in a humanized ILC2 mouse model.

CONCLUSION:

These findings suggest that peripheral expansion of induced Treg cells can serve as a promising therapeutic target against ILC2-dependent asthma.

KEYWORDS:

IL-13; IL-5; Type 2 innate lymphoid cells; airway hyperreactivity; asthma; inducible T-cell costimulator; inducible T-cell costimulator ligand; regulatory T cells

PMID:
27717665
PMCID:
PMC5378695
DOI:
10.1016/j.jaci.2016.08.034
[Indexed for MEDLINE]
Free PMC Article

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