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Biosci. (Landmark Ed)"],"abstract":"<jats:p>Background: Hepatitis B virus (HBV)-specific CD8+ T cells play a crucial role in viral clearance. However, in patients with chronic hepatitis B infections, sustained immune activation leads to functional impairment of these HBV-specific CD8+ T cells. The goal of this study was to clarify whether these virus-specific CD8+ T cells are exhausted or reflect an incomplete response derived from the initial T cell repertoire. Methods: In this study, HBV core 18\u201327 epitope-specific CD8+ T cells were identified by proliferation through in vitro antigen stimulation. Peptide-specific CD8+ T cells recognizing the cytomegalovirus (CMV) pp65 495\u2013503 epitope were used as a positive control, as they exhibit a robust immune response. Single-cell sequencing was employed to characterize the TCR repertoire of expanded clones. Correlations between T cell subsets and clinical outcomes were analyzed and compared. Results: Both HBV core 18\u201327-specific and CMV pp65-specific CD8+ T cells were successfully classified into three functionally distinct subsets: IFN\u03b3+, mTGF\u03b2+, and IFN\u03b3\u2013\/mTGF\u03b2\u2013. Those patients with resolved acute HBV infections and HBV core 18\u201327 specific CD8+ T cells exhibited the highest IFN\u03b3+\/mTGF\u03b2+ ratio, reaching levels comparable to those of CMV pp65-specific CD8+ T cells. Inactive HBV carriers exhibited the second-highest IFN\u03b3+\/mTGF\u03b2+ ratio, while this ratio was lowest among patients exhibiting viral immune tolerance. HBV core 18\u201327 tetramer staining and ERGO-\u2161 Model prediction demonstrated that IFN\u03b3+ subset CD8+ T cells exhibited the highest affinity for this epitope, followed by the mTGF\u03b2+ subset, with IFN\u03b3\u2013\/mTGF\u03b2\u2013 cells exhibiting the lowest affinity. Conclusions: These results suggest that individuals with a high IFN\u03b3+\/mTGF\u03b2+ ratio exhibit a lower HBV viral load. The IFN\u03b3+\/mTGF\u03b2+ CD8+ T cell ratio, in particular, appears to be associated with HBV clearance, and this may be attributable to T cell receptor affinity for HBV epitopes.<\/jats:p>","DOI":"10.31083\/fbl51459","type":"journal-article","created":{"date-parts":[[2026,5,30]],"date-time":"2026-05-30T07:25:36Z","timestamp":1780125936000},"source":"Crossref","is-referenced-by-count":0,"title":["Functional Heterogeneity of Hepatitis B Virus-Specific CD8+ T Cells Mediates the Clinical Outcomes of Infection"],"prefix":"10.31083","volume":"31","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-2935-6440","authenticated-orcid":true,"given":"Zhijun","family":"Shen","sequence":"first","affiliation":[{"name":"Department of Immunology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, 430030 Wuhan, Hubei, China"},{"name":"Department of Clinical Laboratory, Hubei No.3 People\u2019s Hospital of Jianghan University, 430033 Wuhan, Hubei, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Immunology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, 430030 Wuhan, Hubei, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Immunology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, 430030 Wuhan, Hubei, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3774-9624","authenticated-orcid":true,"given":"Mi","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Immunology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, 430030 Wuhan, Hubei, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7759-4586","authenticated-orcid":true,"given":"Ting","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Immunology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, 430030 Wuhan, Hubei, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6283-9096","authenticated-orcid":true,"given":"Lichen","family":"Ouyang","sequence":"additional","affiliation":[{"name":"Department of Immunology, School of Medicine, Jianghan University, 430056 Wuhan, Hubei, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-3618-0532","authenticated-orcid":true,"given":"Xiufang","family":"Weng","sequence":"additional","affiliation":[{"name":"Department of Immunology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, 430030 Wuhan, Hubei, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-8157-2157","authenticated-orcid":true,"given":"Shiguo","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Clinical Laboratory, Hubei No.3 People\u2019s Hospital of Jianghan University, 430033 Wuhan, Hubei, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiongwen","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Immunology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, 430030 Wuhan, Hubei, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"16242","published-online":{"date-parts":[[2026,5,21]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","unstructured":"Burki T. 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