Mechanisms of allergy and clinical immunology
Dysregulation of type 2 innate lymphoid cells and TH2 cells impairs pollutant-induced allergic airway responses

https://doi.org/10.1016/j.jaci.2016.03.044Get rights and content
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Background

Although the prominent role of TH2 cells in type 2 immune responses is well established, the newly identified type 2 innate lymphoid cells (ILC2s) can also contribute to orchestration of allergic responses. Several experimental and epidemiologic studies have provided evidence that allergen-induced airway responses can be further enhanced on exposure to environmental pollutants, such as diesel exhaust particles (DEPs). However, the components and pathways responsible remain incompletely known.

Objective

We sought to investigate the relative contribution of ILC2 and adaptive TH2 cell responses in a murine model of DEP-enhanced allergic airway inflammation.

Methods

Wild-type, Gata-3+/nlslacZ (Gata-3–haploinsufficient), RAR-related orphan receptor α (RORα)fl/flIL7RCre (ILC2-deficient), and recombination-activating gene (Rag) 2−/− mice were challenged with saline, DEPs, or house dust mite (HDM) or DEP+HDM. Airway hyperresponsiveness, as well as inflammation, and intracellular cytokine expression in ILC2s and TH2 cells in the bronchoalveolar lavage fluid and lung tissue were assessed.

Results

Concomitant DEP+HDM exposure significantly enhanced allergic airway inflammation, as characterized by increased airway eosinophilia, goblet cell metaplasia, accumulation of ILC2s and TH2 cells, type 2 cytokine production, and airway hyperresponsiveness compared with sole DEPs or HDM. Reduced Gata-3 expression decreased the number of functional ILC2s and TH2 cells in DEP+HDM-exposed mice, resulting in an impaired DEP-enhanced allergic airway inflammation. Interestingly, although the DEP-enhanced allergic inflammation was marginally reduced in ILC2-deficient mice that received combined DEP+HDM, it was abolished in DEP+HDM-exposed Rag2−/− mice.

Conclusion

These data indicate that dysregulation of ILC2s and TH2 cells attenuates DEP-enhanced allergic airway inflammation. In addition, a crucial role for the adaptive immune system was shown on concomitant DEP+HDM exposure.

Key words

Diesel exhaust particles
house dust mite
type 2 innate lymphoid cell
TH2 response
asthma

Abbreviations used

AHR
Airway hyperresponsiveness
BALF
Bronchoalveolar lavage fluid
DC
Dendritic cell
DEPs
Diesel exhaust particles
HDM
House dust mite
ILC2
Type 2 innate lymphoid cell
MHCII
MHC class II
MLN
Mediastinal lymph node
Rag
Recombination-activating gene
RORα
RAR-related orphan receptor α
TCR
T-cell receptor
TSLP
Thymic stromal lymphopoietin
WT
Wild type

Cited by (0)

Supported by the Interuniversity Attraction Poles Programme (IUAP), Belgian state; Belgian Science Policy (P7/30), Concerted Research Action of the Ghent University (BOF/GOA 01G02714); Fund for Scientific Research–Flanders (FWO-Vlaanderen); and Lung Foundation Netherlands (to R.W.H.). S.P. is a postdoctoral researcher of the Fund for Scientific Research–Flanders.

Disclosure of potential conflict of interest: R. W. Hendriks receives research support from the Lung Foundation, The Netherlands. A. N. J. McKenzie receives project funding form Janssen and MedImmune and receives royalties from Janssen. T. Maes receives travel support from GlaxoSmithKline and Boehringer Ingelheim. G. G. Brusselle serves as a board member for AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Novartis, and Sanofi and receives payment for lectures from AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Novartis, Pfizer, and Teva. G. F. Joos receives research funding from BelSPO and FWO Flanders; serves as a consultant for AstraZeneca, GlaxoSmithKline, and Novartis; and receives payments for lectures from AstraZeneca, GlaxoSmithKline, Novartis, SandozPharma, Novartis, and Sandoz Pharma and travel support from AstraZeneca and Novartis. The rest of the authors declare that they have no relevant conflicts of interest.

These authors contributed equally to this work.

These authors contributed equally to this work.