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Immunol."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>Prolonged viral infections often lead to lymphocyte exhaustion, marked by heightened inhibitory receptor expression like PD-1, compromising host defense mechanisms. The unexplored potential of chemical checkpoint inhibitors in rejuvenating immune responses prompted our investigation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We focused on CCT007093, a Wip1 inhibitor, screened for its distinctive capacity to simultaneously decrease PD-1 and Fc\u03b3RIIB expression in B cells.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>In this study, we harnessed a murine model of immune exhaustion induced by chronic hepatitis B virus (HBV) infection using hydrodynamic injection. Treatment with CCT007093 resulted in decreased levels of PD-1 expression, resulting in reduced percentages of PD-1<jats:sup>+\/hi<\/jats:sup> CD4<jats:sup>+<\/jats:sup> and CD8<jats:sup>+<\/jats:sup> T cells in circulation, spleen, and liver. The expression levels of PD-1 and Fc\u03b3RIIB, along with the percentages of PD-1<jats:sup>+\/hi<\/jats:sup> and Fc\u03b3RIIB<jats:sup>+\/hi<\/jats:sup> CD19<jats:sup>+<\/jats:sup> B cells in these tissues, were similarly diminished. Moreover, intrahepatic lymphocytes treated with CCT007093 displayed heightened responsiveness to <jats:italic>ex vivo<\/jats:italic> activation. Consequently, mice treated with CCT007093 exhibited significantly reduced serum HBsAg levels compared to vehicle-treated mice. Our detailed analyses, spanning promoter and transcriptome evaluations, uncovered p65 NF-\u03baB as the primary activator of  T cells and B cells, while Ying Yang 1 (YY1) emerged as the key regulator, orchestrating the down-regulation of PD-1 and Fc\u03b3RIIB gene transcription in response to CCT007093.<\/jats:p><\/jats:sec><jats:sec><jats:title>Discussion<\/jats:title><jats:p>Our study highlights the prowess of chemical checkpoint inhibitors, exemplified by CCT007093, in alleviating immune exhaustion in HBV-infected mice, particularly by enhancing adaptive immunity.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2025.1548814","type":"journal-article","created":{"date-parts":[[2025,5,9]],"date-time":"2025-05-09T05:34:50Z","timestamp":1746768890000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Wip1 inhibitor CCT007093 alleviates immune exhaustion of lymphocytes via p65 NF-\u03baB and YY1 in chronic hepatitis B virus infection in mice"],"prefix":"10.3389","volume":"16","author":[{"given":"Yu-Syuan","family":"You","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wan-Ting","family":"Chang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chia-Lang","family":"Hsu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui-Ying","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan-Fong","family":"Lu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"InKyeom","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shiang-Jong","family":"Tzeng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,5,9]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1038\/nri3862","article-title":"Molecular and cellular insights into T cell exhaustion","volume":"15","author":"Wherry","year":"2015","journal-title":"Nat Rev Immunol"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1111\/imm.13464","article-title":"NK-cell exhaustion, B-cell exhaustion and T-cell exhaustion-the differences and similarities","volume":"166","author":"Roe","year":"2022","journal-title":"Immunology"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1016\/j.molimm.2007.07.038","article-title":"PD-1 upregulation is associated with HBV-specific T cell dysfunction in chronic hepatitis B patients","volume":"45","author":"Peng","year":"2008","journal-title":"Mol Immunol"},{"key":"B4","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1186\/s12865-019-0309-9","article-title":"CD4+ T cell exhaustion revealed by high PD-1 and LAG-3 expression and the loss of helper T cell function in chronic hepatitis B","volume":"20","author":"Dong","year":"2019","journal-title":"BMC Immunol"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1172\/JCI45685","article-title":"Attenuation of HIV-associated human B cell exhaustion by siRNA downregulation of inhibitory receptors","volume":"121","author":"Kardava","year":"2011","journal-title":"J Clin Invest"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1038\/nature05115","article-title":"R. 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