Xiaowen Wang1, Qingyang Dong2, Qian Li3, Yuanyuan Li4, Dianyuan Zhao2, Jinjie Sun5, Junliang Fu4, Fanping Meng4, Hu Lin4, Junjie Luan4, Biao Liu2, Min Wang2, Fu-Sheng Wang4, Fuchu He6, Li Tang7. 1. State Key Laboratory of Proteomics, National Center for Protein Sciences, Beijing, Beijing Proteome Research Center, Beijing Institute of Lifeomics, Beijing, P.R. China; School of Life Sciences, Peking University, Beijing, P.R. China. 2. State Key Laboratory of Proteomics, National Center for Protein Sciences, Beijing, Beijing Proteome Research Center, Beijing Institute of Lifeomics, Beijing, P.R. China. 3. Department of Biochemistry and Molecular Biology, Anhui Medical University, Hefei, Anhui Province, P.R. China; Institutes of Biomedical Sciences, Fudan University, Shanghai, P.R. China. 4. Center of Infectious Disease, Beijing 302 Hospital, Beijing, P.R. China. 5. Air Force General Hospital, PLA, Beijing, P.R. China. 6. State Key Laboratory of Proteomics, National Center for Protein Sciences, Beijing, Beijing Proteome Research Center, Beijing Institute of Lifeomics, Beijing, P.R. China; School of Life Sciences, Peking University, Beijing, P.R. China; Institutes of Biomedical Sciences, Fudan University, Shanghai, P.R. China. Electronic address: hefc@nic.bmi.ac.cn. 7. State Key Laboratory of Proteomics, National Center for Protein Sciences, Beijing, Beijing Proteome Research Center, Beijing Institute of Lifeomics, Beijing, P.R. China; Department of Biochemistry and Molecular Biology, Anhui Medical University, Hefei, Anhui Province, P.R. China. Electronic address: tangli08@aliyun.com.
Abstract
BACKGROUND & AIMS: Production of neutralizing antibodies against hepatitis B surface antigen (HBsAg) is dysregulated in patients with persistent hepatitis B virus (HBV) infection. We investigated mechanisms by which this immune response to the virus is disrupted and whether it can be restored to promote clearance of HBV. METHODS: Immune-competent C57BL/6N and C57BL/6J, as well as mice deficient in follicular helper T cells (Tfh-cell-deficient), B cells, or Foxp3+ T-regulatory cells (Treg cell deficient), were given hydrodynamic injections of pAAV/HBV1.2 plasmids. Some mice were given injections of sorted Tfh cells, pan-B cells, Treg cells, or a blocking antibody against CTLA4. Production of antibodies against HBsAg and clearance of HBV were assessed by flow cytometry, enzyme-linked immunosorbent assay, polymerase chain reaction, and immunohistochemical analyses. We obtained blood samples from patients with HBV infection and isolated Treg cells. We measured the ability of Treg cells to suppress production of interleukin 21 (IL21) in CD4+ T cells. RESULTS: Immune-competent C57BL/6N and C57BL/6J mice transfected with the plasmid encoding HBV had features of viral clearance and viral persistence observed in humans. A Tfh-cell response to HBsAg was required for clearance of HBV and was suppressed by Treg cells in mice with persistent HBV infection. Depletion of Treg cells or inhibition of Treg-cell function (with blocking antibody against CTLA4) restored the Tfh-cell response against HBsAg and clearance of HBV in mice. Impaired Tfh-cell response to HBsAg was observed in blood from patients with chronic HBV infection, responsiveness was restored by depletion of Treg cells or blocking antibody against CTLA4. CONCLUSIONS: In studies of HBV-infected mice and blood from patients with chronic HBV infection, we found a Tfh-cell response to HBsAg of to be required for HBV clearance, and that this response was blocked by Treg cells. Inhibiting Treg-cell activity using neutralizing antibody against CTLA4 restored the ability of Tfh cells to clear HBV infection; this approach might be developed for treatment of patients with chronic HBV infection.
BACKGROUND & AIMS: Production of neutralizing antibodies against hepatitis B surface antigen (HBsAg) is dysregulated in patients with persistent hepatitis B virus (HBV) infection. We investigated mechanisms by which this immune response to the virus is disrupted and whether it can be restored to promote clearance of HBV. METHODS: Immune-competent C57BL/6N and C57BL/6J, as well as mice deficient in follicular helper T cells (Tfh-cell-deficient), B cells, or Foxp3+ T-regulatory cells (Treg cell deficient), were given hydrodynamic injections of pAAV/HBV1.2 plasmids. Some mice were given injections of sorted Tfh cells, pan-B cells, Treg cells, or a blocking antibody against CTLA4. Production of antibodies against HBsAg and clearance of HBV were assessed by flow cytometry, enzyme-linked immunosorbent assay, polymerase chain reaction, and immunohistochemical analyses. We obtained blood samples from patients with HBV infection and isolated Treg cells. We measured the ability of Treg cells to suppress production of interleukin 21 (IL21) in CD4+ T cells. RESULTS: Immune-competent C57BL/6N and C57BL/6J mice transfected with the plasmid encoding HBV had features of viral clearance and viral persistence observed in humans. A Tfh-cell response to HBsAg was required for clearance of HBV and was suppressed by Treg cells in mice with persistent HBV infection. Depletion of Treg cells or inhibition of Treg-cell function (with blocking antibody against CTLA4) restored the Tfh-cell response against HBsAg and clearance of HBV in mice. Impaired Tfh-cell response to HBsAg was observed in blood from patients with chronic HBV infection, responsiveness was restored by depletion of Treg cells or blocking antibody against CTLA4. CONCLUSIONS: In studies of HBV-infectedmice and blood from patients with chronic HBV infection, we found a Tfh-cell response to HBsAg of to be required for HBV clearance, and that this response was blocked by Treg cells. Inhibiting Treg-cell activity using neutralizing antibody against CTLA4 restored the ability of Tfh cells to clear HBV infection; this approach might be developed for treatment of patients with chronic HBV infection.
Authors: Loghman Salimzadeh; Nina Le Bert; Charles-A Dutertre; Upkar S Gill; Evan W Newell; Christian Frey; Magdeleine Hung; Nikolai Novikov; Simon Fletcher; Patrick Tf Kennedy; Antonio Bertoletti Journal: J Clin Invest Date: 2018-08-07 Impact factor: 14.808
Authors: Alice R Burton; Laura J Pallett; Laura E McCoy; Kornelija Suveizdyte; Oliver E Amin; Leo Swadling; Elena Alberts; Brian R Davidson; Patrick Tf Kennedy; Upkar S Gill; Claudia Mauri; Paul A Blair; Nadege Pelletier; Mala K Maini Journal: J Clin Invest Date: 2018-08-09 Impact factor: 19.456