Early introduction of IL-10 weakens BCG revaccination’s protection by suppressing CD4+Th1 cell responses
Abstract Background The Bacillus Calmette-Guérin (BCG) vaccine, currently the sole authorized vaccine against tuberculosis (TB), demonstrates limited effectiveness in safeguarding adolescents and adults from active TB, even when administered as a booster with either BCG itself or heterologous vaccin...
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BMC
2024-12-01
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| Series: | Journal of Translational Medicine |
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| Online Access: | https://doi.org/10.1186/s12967-024-05683-w |
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| author | Qing Lei Hui Fu Zongjie Yao Zijie Zhou Yueqing Wang Xiaosong Lin Yin Yuan Qi Ouyang Xinyue Xu Jinge Cao Mengze Gan Xionglin Fan |
| author_facet | Qing Lei Hui Fu Zongjie Yao Zijie Zhou Yueqing Wang Xiaosong Lin Yin Yuan Qi Ouyang Xinyue Xu Jinge Cao Mengze Gan Xionglin Fan |
| author_sort | Qing Lei |
| collection | DOAJ |
| description | Abstract Background The Bacillus Calmette-Guérin (BCG) vaccine, currently the sole authorized vaccine against tuberculosis (TB), demonstrates limited effectiveness in safeguarding adolescents and adults from active TB, even when administered as a booster with either BCG itself or heterologous vaccine candidates. To effectively control the persistent epidemic of adult TB, it is imperative to investigate the mechanisms responsible for the suboptimal efficacy of the BCG prime-boosting strategy against primary Mycobacterium tuberculosis (M.tb) infection. Methods C57BL/6J mice were immunized with the BCG vaccine either once or twice, followed by analysis of lung tissue to assess changes in cytokine levels. Additionally, varying intervals between vaccinations and detection times were examined to study IL-10 expression across different organs. IL-10-expressing cells in the lungs, spleen, and lymph nodes were analyzed through FACS and intracellular cytokine staining (ICS). BCG-revaccinated IL-10 −/− mutant mice were compared with wild-type mice to evaluate antigen-specific IgG antibody and T cell responses. Protection against M.tb aerosol challenge was evaluated in BCG-revaccinated mice, either untreated or treated with anti-IL-10R monoclonal antibody. Results IL-10 was significantly upregulated in the lungs of BCG-revaccinated mice shortly after the booster immunization. IL-10 expression peaked in the lungs 3–6 weeks post-revaccination and was also detected in lymph nodes and spleen as early as 2 weeks following the booster dose, regardless of the intervals between the prime and booster vaccinations. The primary sources of IL-10 in these tissues were identified as macrophages and dendritic cells. Blocking IL-10 signaling in BCG-revaccinated mice—either by using IL-10 −/− mutant mice or administering anti-IL-10R monoclonal antibody increased levels of antigen-specific IFN-γ+ or IL-2+ CD4+ T cells, enhanced central and effector memory CD4+ T cell responses, and provided better protection against aerosol infection with 300 CFUs of M.tb. Conclusion Our findings are crucial for formulating effective immunization strategies related to the BCG vaccine and for developing efficacious adult TB vaccines. Graphical abstract |
| format | Article |
| id | doaj-art-c83eb74d14ef4f3fbf48bf754e04d77f |
| institution | Kabale University |
| issn | 1479-5876 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | BMC |
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| series | Journal of Translational Medicine |
| spelling | doaj-art-c83eb74d14ef4f3fbf48bf754e04d77f2024-12-08T12:44:41ZengBMCJournal of Translational Medicine1479-58762024-12-0122111410.1186/s12967-024-05683-wEarly introduction of IL-10 weakens BCG revaccination’s protection by suppressing CD4+Th1 cell responsesQing Lei0Hui Fu1Zongjie Yao2Zijie Zhou3Yueqing Wang4Xiaosong Lin5Yin Yuan6Qi Ouyang7Xinyue Xu8Jinge Cao9Mengze Gan10Xionglin Fan11Department of Pathogen Biology, School of Basic Medicine, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Hubei Key Laboratory of Drug Target Research and Pharmacodynamic Evaluation, Huazhong University of Science and TechnologyDepartment of Pathogen Biology, School of Basic Medicine, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Hubei Key Laboratory of Drug Target Research and Pharmacodynamic Evaluation, Huazhong University of Science and TechnologyDepartment of Pathogen Biology, School of Basic Medicine, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Hubei Key Laboratory of Drug Target Research and Pharmacodynamic Evaluation, Huazhong University of Science and TechnologyDepartment of Pathogen Biology, School of Basic Medicine, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Hubei Key Laboratory of Drug Target Research and Pharmacodynamic Evaluation, Huazhong University of Science and TechnologyDepartment of Laboratory Medicine, Wuhan No. 1 Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Pathogen Biology, School of Basic Medicine, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Hubei Key Laboratory of Drug Target Research and Pharmacodynamic Evaluation, Huazhong University of Science and TechnologyDepartment of Pediatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Pathogen Biology, School of Basic Medicine, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Hubei Key Laboratory of Drug Target Research and Pharmacodynamic Evaluation, Huazhong University of Science and TechnologyDepartment of Pathogen Biology, School of Basic Medicine, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Hubei Key Laboratory of Drug Target Research and Pharmacodynamic Evaluation, Huazhong University of Science and TechnologyDepartment of Pathogen Biology, School of Basic Medicine, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Hubei Key Laboratory of Drug Target Research and Pharmacodynamic Evaluation, Huazhong University of Science and TechnologyDepartment of Pathogen Biology, School of Basic Medicine, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Hubei Key Laboratory of Drug Target Research and Pharmacodynamic Evaluation, Huazhong University of Science and TechnologyDepartment of Pathogen Biology, School of Basic Medicine, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Hubei Key Laboratory of Drug Target Research and Pharmacodynamic Evaluation, Huazhong University of Science and TechnologyAbstract Background The Bacillus Calmette-Guérin (BCG) vaccine, currently the sole authorized vaccine against tuberculosis (TB), demonstrates limited effectiveness in safeguarding adolescents and adults from active TB, even when administered as a booster with either BCG itself or heterologous vaccine candidates. To effectively control the persistent epidemic of adult TB, it is imperative to investigate the mechanisms responsible for the suboptimal efficacy of the BCG prime-boosting strategy against primary Mycobacterium tuberculosis (M.tb) infection. Methods C57BL/6J mice were immunized with the BCG vaccine either once or twice, followed by analysis of lung tissue to assess changes in cytokine levels. Additionally, varying intervals between vaccinations and detection times were examined to study IL-10 expression across different organs. IL-10-expressing cells in the lungs, spleen, and lymph nodes were analyzed through FACS and intracellular cytokine staining (ICS). BCG-revaccinated IL-10 −/− mutant mice were compared with wild-type mice to evaluate antigen-specific IgG antibody and T cell responses. Protection against M.tb aerosol challenge was evaluated in BCG-revaccinated mice, either untreated or treated with anti-IL-10R monoclonal antibody. Results IL-10 was significantly upregulated in the lungs of BCG-revaccinated mice shortly after the booster immunization. IL-10 expression peaked in the lungs 3–6 weeks post-revaccination and was also detected in lymph nodes and spleen as early as 2 weeks following the booster dose, regardless of the intervals between the prime and booster vaccinations. The primary sources of IL-10 in these tissues were identified as macrophages and dendritic cells. Blocking IL-10 signaling in BCG-revaccinated mice—either by using IL-10 −/− mutant mice or administering anti-IL-10R monoclonal antibody increased levels of antigen-specific IFN-γ+ or IL-2+ CD4+ T cells, enhanced central and effector memory CD4+ T cell responses, and provided better protection against aerosol infection with 300 CFUs of M.tb. Conclusion Our findings are crucial for formulating effective immunization strategies related to the BCG vaccine and for developing efficacious adult TB vaccines. Graphical abstracthttps://doi.org/10.1186/s12967-024-05683-wBCG revaccinationBCG prime-boost strategyAdult tuberculosisPrimary Mycobacterium tuberculosis infectionIL-10 inhibitionMemory CD4+ T cell |
| spellingShingle | Qing Lei Hui Fu Zongjie Yao Zijie Zhou Yueqing Wang Xiaosong Lin Yin Yuan Qi Ouyang Xinyue Xu Jinge Cao Mengze Gan Xionglin Fan Early introduction of IL-10 weakens BCG revaccination’s protection by suppressing CD4+Th1 cell responses Journal of Translational Medicine BCG revaccination BCG prime-boost strategy Adult tuberculosis Primary Mycobacterium tuberculosis infection IL-10 inhibition Memory CD4+ T cell |
| title | Early introduction of IL-10 weakens BCG revaccination’s protection by suppressing CD4+Th1 cell responses |
| title_full | Early introduction of IL-10 weakens BCG revaccination’s protection by suppressing CD4+Th1 cell responses |
| title_fullStr | Early introduction of IL-10 weakens BCG revaccination’s protection by suppressing CD4+Th1 cell responses |
| title_full_unstemmed | Early introduction of IL-10 weakens BCG revaccination’s protection by suppressing CD4+Th1 cell responses |
| title_short | Early introduction of IL-10 weakens BCG revaccination’s protection by suppressing CD4+Th1 cell responses |
| title_sort | early introduction of il 10 weakens bcg revaccination s protection by suppressing cd4 th1 cell responses |
| topic | BCG revaccination BCG prime-boost strategy Adult tuberculosis Primary Mycobacterium tuberculosis infection IL-10 inhibition Memory CD4+ T cell |
| url | https://doi.org/10.1186/s12967-024-05683-w |
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