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Thus, there is an unmet need for new therapies aimed at CHB. This study comprised two clinical trials, including 130 CHB patients, who were treatment-na\u00efve; in the first, 92 patients were systematically analyzed ex vivo for interleukin-2 receptor (IL-2R) expression and inhibitory molecules expression after receiving Peg-IFN-\u03b1-2b therapy. In our second clinical trial, 38 non-responder patients, in whom IFN-\u03b1 therapy had failed, were treated with or without low-dose IL-2 for 24 weeks. We then examined the hepatitis B virus (HBV)-specific CD8\n                    <jats:sup>+<\/jats:sup>\n                    T-cell response and the clinical outcome, in these patients. Although the majority of the participants undergoing Peg-IFN-\u03b1-2b therapy were non-responders, we observed a decrease in CD25 expression on their CD4\n                    <jats:sup>+<\/jats:sup>\n                    T cells, suggesting that IFN-\u03b1 therapy may provide a rationale for sequential IL-2 treatment without increasing regulatory T cells (Tregs). Following sequential therapy with IL-2, we demonstrated that the non-responders experienced a decrease in the numbers of Tregs and programmed cell death protein 1 (PD-1) expression. In addition, sequential IL-2 administration rescued effective immune function, involving signal transducer and activator of transcription 1 (STAT1) activation. Importantly, IL-2 therapy significantly increased the frequency and function of HBV-specific CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cells, which translated into improved clinical outcomes, including HBeAg seroconversion, among the non-responder CHB patients. Our findings suggest that sequential IL-2 therapy shows efficacy in rescuing immune function in non-responder patients with refractory CHB.\n                  <\/jats:p>","DOI":"10.1038\/s41392-021-00776-0","type":"journal-article","created":{"date-parts":[[2021,11,4]],"date-time":"2021-11-04T21:02:36Z","timestamp":1636059756000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":59,"title":["Restoration of HBV-specific CD8+ T-cell responses by sequential low-dose IL-2 treatment in non-responder patients after IFN-\u03b1 therapy"],"prefix":"10.1038","volume":"6","author":[{"given":"Dongyao","family":"Wang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Binqing","family":"Fu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaokun","family":"Shen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chuang","family":"Guo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanyan","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junfei","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rui","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Ye","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiabin","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhigang","family":"Tian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haiming","family":"Wei","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,11,5]]},"reference":[{"key":"776_CR1","doi-asserted-by":"publisher","first-page":"383","DOI":"10.1016\/S2468-1253(18)30056-6","volume":"3","author":"D Razavi-Shearer","year":"2018","unstructured":"Razavi-Shearer, D. et al. 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