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 3

iNKT cell deficiency exacerbates PM2.5-induced pulmonary inflammation and IL-17A production.

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iNKT cell deficiency exacerbates PM2.5-induced pulmonary inflammation an...
(A–F) BALB/c (WT) mice received daily i.n. exposure of PM2.5 for 3 days and were sacrificed 1 day after the last exposure. (A) Representative flow cytometry plot showing CD4+ and CD4– iNKT cell subsets, gated from TCRβ+CD1d-tetramer+ (tet+) cells. (B) Total number of lung iNKT cells, assessed as in A. (C) Relative percentages of CD4+ and CD4– iNKT cell subsets, assessed as in A. (D) Representative flow cytometry plot showing CD69 expression on CD4+ and CD4– iNKT cell subsets, gated from TCRβ+CD1d-tet+ cells. (E) Total number of CD69+ iNKT cells, assessed as in D. (F) Relative percentages of CD69-expressing CD4+ and CD4– iNKT cell subsets, assessed as in D. (G) Representative histogram (top panel) and frequency (bottom panel) of annexin V+ MLE-12 cells after treatment with 300 μg/mL PM2.5 for 6 hours. (H–J) WT mice received daily i.n. exposure of PM2.5, as in A. (H) Representative histogram showing Tim-1 expression on total, CD4+, and CD4– iNKT cells. (I) Total number of Tim-1+ iNKT cells, assessed as in H. (J) Relative percentages of Tim-1–expressing CD4+ and CD4– iNKT cell subsets, assessed as in H. (K) Flow histogram showing CD69 expression on iNKT cells cocultured with unexposed or PM2.5-exposed MLE-12 cells in the presence or absence of annexin V. (L) Total CD69+ iNKT cells, assessed as in K. Data are shown as mean ± SEM from 2 independent experiments (n = 5 per group) (B–F, I, and J) or mean ± SD from 1 representative experiment (n = 3 wells) with consistent findings (G and L). Statistical analysis was performed using an unpaired 2-tailed t test. *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001. Ctrl, control; ISO, isotype; Max, maximum.