{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,1]],"date-time":"2026-08-01T15:16:21Z","timestamp":1785597381068,"version":"3.56.0"},"reference-count":33,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,11,25]],"date-time":"2021-11-25T00:00:00Z","timestamp":1637798400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["JP18K15953"],"award-info":[{"award-number":["JP18K15953"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>Bronchial epithelial cells are front sentinels eliciting innate and adaptive immunity to respiratory viral pathogens. Recognition of viral double-stranded RNA induces antiviral interferon (IFN) responses in bronchial epithelial cells. Co-inhibitory molecules programmed cell death 1 ligand 1 (PD-L1) and ligand 2 (PD-L2) were also induced on bronchial epithelial cells, which bind programmed cell death 1 on T cell and inhibit the function of virus-specific cytotoxic T lymphocyte. A previous study showed that antiviral type I IFN increased PD-L1 and PD-L2 expression in cultured melanoma cells. However, it remains unknown whether antiviral IFNs affect PD-L1 and PD-L2 expression in bronchial epithelial cells. In addition, we previously reported that inhibition of PI3K\u03b4 signaling enhanced antiviral IFN responses in human primary bronchial epithelial cells (PBECs). Here we assessed the effect of exogenous IFNs or a selective PI3K\u03b4 inhibitor IC87114 on PD-L1 and PD-L2 in PBECs stimulated with a synthetic double-stranded RNA poly I:C or human metapneumovirus. Treatment with IFN\u03b2 or IFN\u03bb increased PD-L1 and PD-L2, and IFN\u03b2 or IFN\u03bb treatment plus poly I:C further increased both expressions. Treatment with IC87114 or transfection with siRNA targeting PI3K p110\u03b4 enhanced poly I:C\u2013induced gene and protein expression of PD-L2, whereas IC87114 suppressed poly I:C\u2013induced PD-L1. IC87114 enhanced poly I:C\u2013induced gene expression of IFN\u03b2, IFN\u03bb, and IFN-regulated genes <jats:italic>via<\/jats:italic> increased TBK1 and IRF3 phosphorylation. Transfection with siIRF3 counteracted the enhancement of poly I:C\u2013induced PD-L2 by IC87114, whereas IC87114 suppressed poly I:C\u2013induced PD-L1 regardless of transfection with siNC or siIRF3. Similar effects of IC87114 on PD-L1 and PD-L2 expression were observed in human metapneumovirus\u2013infected PBECs. We showed for the first time that type I and type III IFNs induced the expression of PD-L1 and PD-L2 in PBECs. Our findings suggest that during viral infections, inhibition of PI3K\u03b4 differentially regulates PD-L1 and PD-L2 expression in bronchial epithelial cells.<\/jats:p>","DOI":"10.3389\/fimmu.2021.767666","type":"journal-article","created":{"date-parts":[[2021,12,1]],"date-time":"2021-12-01T02:16:55Z","timestamp":1638325015000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":7,"title":["Inhibition of PI3K\u03b4 Differentially Regulates Poly I:C\u2013 and Human Metapneumovirus\u2013Induced PD\u2013L1 and PD\u2013L2 Expression in Human Bronchial Epithelial 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