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DOI: 10.1038/s41590-020-0745-y
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In this study, the authors used Bcl11b-tdTomato reporter mice, which specifically label ILC2s in the Lin− population of the lung. They isolated Lin−CD45+IL-7Rα+ Bcl11b-tdTomato+ ILC2s from the lungs of both Bcl11btdTomato/tdTomato and Pdcd1−/−;Bcl11btdTomato/+ mice to investigate ILC2 heterogeneity and activation pathways. The samples were collected at three time points: days 0, 7, and 14 (d0, d7, and d14) following four consecutive papain intranasal challenges. The analysis revealed four distinct ILC2 subsets, including two non-activated and two activated subsets, within the inflammatory lung. Among the activated subsets, one showed better viability and was detectable at both d7 and d14, indicating its ability to persist during the resolution phase. The other, observed only at d7, was more activated, proliferative, and enriched for genes associated with migration, wound healing, and immune memory. Notably, the subset with both Trm and Tcm/Tem transcriptomic signatures exhibited significantly higher expression of the nuclear receptor transcription factor Nr4a1 and the surface molecule CD69. Pdcd1, a direct target of Nr4a1, was the only immune inhibitory gene examined that was highly expressed in the Nr4a1+ ILC2 subset. To explore the role of PD-1 in these cells under acute lung inflammation, the authors analyzed the transcriptomes of PD-1 KO Nr4a1+ ILC2s. They found that the PD-1 KO Nr4a1+ ILC2s exhibited similar memory, Trm, Tem/Tcm, and wound healing scores compared to control wild-type Nr4a1+ ILC2s, but with an increased frequency of Il5-expressing cells. In contrast, PD-1 KO non-activated ILC2s showed overrepresentation of immune system process pathways, such as "positive regulation of inflammatory response," "TNF signaling pathway," "NF-kappa B signaling pathway," and "oxidative phosphorylation." Overall, these findings suggest that PD-1 acts as a negative regulator of the Nr4a1+ ILC2 subset, influencing its activation, differentiation trajectory, persistence, and metabolism.
DOI: 10.1186/s12915-023-01690-3
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Editor & Reviewer: Congci Yu
