Identification of a PD-L1+Tim-1+ iNKT subset that protects against fine particulate matter–induced airway inflammation
Christina Li-Ping Thio, Alan Chuan-Ying Lai, Jo-Chiao Wang, Po-Yu Chi, Ya-Lin Chang, Yu-Tse Ting, Shih-Yu Chen, Ya-Jen Chang
Christina Li-Ping Thio, Alan Chuan-Ying Lai, Jo-Chiao Wang, Po-Yu Chi, Ya-Lin Chang, Yu-Tse Ting, Shih-Yu Chen, Ya-Jen Chang
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Research Article Immunology Inflammation

Identification of a PD-L1+Tim-1+ iNKT subset that protects against fine particulate matter–induced airway inflammation

Abstract

Although air pollutants such as fine particulate matter (PM2.5) are associated with acute and chronic lung inflammation, the etiology of PM2.5-induced airway inflammation remains poorly understood. Here we report that PM2.5 triggered airway hyperreactivity (AHR) and neutrophilic inflammation with concomitant increases in Th1 and Th17 responses and epithelial cell apoptosis. We found that γδ T cells promoted neutrophilic inflammation and AHR through IL-17A. Unexpectedly, we found that invariant natural killer T (iNKT) cells played a protective role in PM2.5-induced pulmonary inflammation. Specifically, PM2.5 activated a suppressive CD4– iNKT cell subset that coexpressed Tim-1 and programmed cell death ligand 1 (PD-L1). Activation of this suppressive subset was mediated by Tim-1 recognition of phosphatidylserine on apoptotic cells. The suppressive iNKT subset inhibited γδ T cell expansion and intrinsic IL-17A production, and the inhibitory effects of iNKT cells on the cytokine-producing capacity of γδ T cells were mediated in part by PD-1/PD-L1 signaling. Taken together, our findings underscore a pathogenic role for IL-17A–producing γδ T cells in PM2.5-elicited inflammation and identify PD-L1+Tim-1+CD4– iNKT cells as a protective subset that prevents PM2.5-induced AHR and neutrophilia by inhibiting γδ T cell function.

Authors

Christina Li-Ping Thio, Alan Chuan-Ying Lai, Jo-Chiao Wang, Po-Yu Chi, Ya-Lin Chang, Yu-Tse Ting, Shih-Yu Chen, Ya-Jen Chang

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Figure 6

iNKT cells suppress IL-17A production by γδ T cells through PD-1/PD-L1 interaction.

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iNKT cells suppress IL-17A production by γδ T cells through PD-1/PD-L1 i...
(A–I) C57BL/6 (WT) mice received daily i.n. exposure of PM2.5 for 3 days and were sacrificed 1 day after the last exposure. (A) A viSNE map showing PD-1 expression in various lymphocytes. (B) Representative flow cytometry plot showing PD-1 expression on γδ T cells (CD3+TCRγδ+ cells) and CD3+TCRγδ– T cells. (C and D) Total number (C) and frequency (D) of PD-1+ γδ T cells, assessed as in B. (E–G) Representative flow cytometry plot (E), relative percentages (F), and total number (G) of PD-L1–expressing CD4+ and/or CD4– iNKT cells. (H and I) Representative histogram (H) and total number (I) of Tim-1+PD-L1+CD4– iNKT cells, assessed as in E. (J–M) WT and Jα18–/– mice were exposed to PM2.5 as in A. Anti–PD-1 or isotype control were administered 1 day before and 1 day after the first exposure to PM2.5. (J and K) Representative flow cytometry plot showing IL-17A+ γδ T cells in WT (J) and Jα18–/– mice (K). (L and M) Frequency of IL-17A–producing (L) and total (M) lung γδ T cells, assessed as in J and K. (N and O) Levels of IL-17A in culture supernatant of γδ T cells cocultured with CD4– iNKT cells under IL-23 (50 ng/mL) and IL-1β (50 ng/mL) stimulation for 48 hours. (N) Anti–PD-1 (10 μg/mL) or anti–PD-L1 (10 μg/mL) was added to the coculture system. (O) Coculture was performed in a Transwell system. Data are expressed as mean ± SEM from 2 independent experiment (n = 5–6 per group) (A–M) or mean ± SD from 1 representative experiment (n = 5 wells for N; n = 3 wells for O) with consistent findings (N and O). In the histograms, the blue solid line indicates the isotype-matched control, and the red solid line indicates Ab staining. Statistical analysis was performed using an unpaired 2-tailed t test (C–I) or 1-way ANOVA (L–O). *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001. Ctrl, control; ISO, isotype; Max, maximum.