CD40 Activation Rescues Antiviral CD8+ T Cells from PD-1-Mediated Exhaustion
The intrahepatic immune environment is normally biased towards tolerance. Nonetheless, effective antiviral immune responses can be induced against hepatotropic pathogens. To examine the immunological basis of this paradox we studied the ability of hepatocellularly expressed hepatitis B virus (HBV) t...
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| Published in | PLoS pathogens Vol. 9; no. 7; p. e1003490 |
|---|---|
| Main Authors | , , , , |
| Format | Journal Article |
| Language | English |
| Published |
United States
Public Library of Science
2013
Public Library of Science (PLoS) |
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| Online Access | Get full text |
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| Abstract | The intrahepatic immune environment is normally biased towards tolerance. Nonetheless, effective antiviral immune responses can be induced against hepatotropic pathogens. To examine the immunological basis of this paradox we studied the ability of hepatocellularly expressed hepatitis B virus (HBV) to activate immunologically naïve HBV-specific CD8⁺ T cell receptor (TCR) transgenic T cells after adoptive transfer to HBV transgenic mice. Intrahepatic priming triggered vigorous in situ T cell proliferation but failed to induce interferon gamma production or cytolytic effector function. In contrast, the same T cells differentiated into cytolytic effector T cells in HBV transgenic mice if Programmed Death 1 (PD-1) expression was genetically ablated, suggesting that intrahepatic antigen presentation per se triggers negative regulatory signals that prevent the functional differentiation of naïve CD8⁺ T cells. Surprisingly, coadministration of an agonistic anti-CD40 antibody (αCD40) inhibited PD-1 induction and restored T cell effector function, thereby inhibiting viral gene expression and causing a necroinflammatory liver disease. Importantly, the depletion of myeloid dendritic cells (mDCs) strongly diminished the αCD40 mediated functional differentiation of HBV-specific CD8⁺ T cells, suggesting that activation of mDCs was responsible for the functional differentiation of HBV-specific CD8⁺ T cells in αCD40 treated animals. These results demonstrate that antigen-specific, PD-1-mediated CD8⁺ T cell exhaustion can be rescued by CD40-mediated mDC-activation. |
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| AbstractList | The intrahepatic immune environment is normally biased towards tolerance. Nonetheless, effective antiviral immune responses can be induced against hepatotropic pathogens. To examine the immunological basis of this paradox we studied the ability of hepatocellularly expressed hepatitis B virus (HBV) to activate immunologically naïve HBV-specific CD8⁺ T cell receptor (TCR) transgenic T cells after adoptive transfer to HBV transgenic mice. Intrahepatic priming triggered vigorous in situ T cell proliferation but failed to induce interferon gamma production or cytolytic effector function. In contrast, the same T cells differentiated into cytolytic effector T cells in HBV transgenic mice if Programmed Death 1 (PD-1) expression was genetically ablated, suggesting that intrahepatic antigen presentation per se triggers negative regulatory signals that prevent the functional differentiation of naïve CD8⁺ T cells. Surprisingly, coadministration of an agonistic anti-CD40 antibody (αCD40) inhibited PD-1 induction and restored T cell effector function, thereby inhibiting viral gene expression and causing a necroinflammatory liver disease. Importantly, the depletion of myeloid dendritic cells (mDCs) strongly diminished the αCD40 mediated functional differentiation of HBV-specific CD8⁺ T cells, suggesting that activation of mDCs was responsible for the functional differentiation of HBV-specific CD8⁺ T cells in αCD40 treated animals. These results demonstrate that antigen-specific, PD-1-mediated CD8⁺ T cell exhaustion can be rescued by CD40-mediated mDC-activation.The intrahepatic immune environment is normally biased towards tolerance. Nonetheless, effective antiviral immune responses can be induced against hepatotropic pathogens. To examine the immunological basis of this paradox we studied the ability of hepatocellularly expressed hepatitis B virus (HBV) to activate immunologically naïve HBV-specific CD8⁺ T cell receptor (TCR) transgenic T cells after adoptive transfer to HBV transgenic mice. Intrahepatic priming triggered vigorous in situ T cell proliferation but failed to induce interferon gamma production or cytolytic effector function. In contrast, the same T cells differentiated into cytolytic effector T cells in HBV transgenic mice if Programmed Death 1 (PD-1) expression was genetically ablated, suggesting that intrahepatic antigen presentation per se triggers negative regulatory signals that prevent the functional differentiation of naïve CD8⁺ T cells. Surprisingly, coadministration of an agonistic anti-CD40 antibody (αCD40) inhibited PD-1 induction and restored T cell effector function, thereby inhibiting viral gene expression and causing a necroinflammatory liver disease. Importantly, the depletion of myeloid dendritic cells (mDCs) strongly diminished the αCD40 mediated functional differentiation of HBV-specific CD8⁺ T cells, suggesting that activation of mDCs was responsible for the functional differentiation of HBV-specific CD8⁺ T cells in αCD40 treated animals. These results demonstrate that antigen-specific, PD-1-mediated CD8⁺ T cell exhaustion can be rescued by CD40-mediated mDC-activation. The intrahepatic immune environment is normally biased towards tolerance. Nonetheless, effective antiviral immune responses can be induced against hepatotropic pathogens. To examine the immunological basis of this paradox we studied the ability of hepatocellularly expressed hepatitis B virus (HBV) to activate immunologically naïve HBV-specific CD8 + T cell receptor (TCR) transgenic T cells after adoptive transfer to HBV transgenic mice. Intrahepatic priming triggered vigorous in situ T cell proliferation but failed to induce interferon gamma production or cytolytic effector function. In contrast, the same T cells differentiated into cytolytic effector T cells in HBV transgenic mice if Programmed Death 1 (PD-1) expression was genetically ablated, suggesting that intrahepatic antigen presentation per se triggers negative regulatory signals that prevent the functional differentiation of naïve CD8 + T cells. Surprisingly, coadministration of an agonistic anti-CD40 antibody (αCD40) inhibited PD-1 induction and restored T cell effector function, thereby inhibiting viral gene expression and causing a necroinflammatory liver disease. Importantly, the depletion of myeloid dendritic cells (mDCs) strongly diminished the αCD40 mediated functional differentiation of HBV-specific CD8 + T cells, suggesting that activation of mDCs was responsible for the functional differentiation of HBV-specific CD8 + T cells in αCD40 treated animals. These results demonstrate that antigen-specific, PD-1-mediated CD8 + T cell exhaustion can be rescued by CD40-mediated mDC-activation. Hepatitis B virus (HBV) infection is responsible for more than 500,000 deaths annually as a result of the immune-mediated chronic liver damage it induces. The HBV specific CD8 + T cell response contributes to the pathogenesis of liver disease and viral clearance, and the failure to induce and/or sustain a vigorous CD8 + T cell response results in viral persistence and causes chronic necroinflammatory liver disease. To understand how the HBV-specific CD8 + T cell response is generated in response to intrahepatically expressed HBV, we generated T cell receptor transgenic mice whose CD8 + T cells are specific for HBV core or HBV envelope antigens. We find that these T cells are primed in the liver when they are adoptively transferred into HBV transgenic mouse recipients whose livers produce infectious virus particles, and that they proliferate vigorously in situ but do not differentiate into functional effector T cells after antigen recognition. Functional differentiation is suppressed by dominant negative regulatory signals, including PD-1, unless they are suppressed by anti-CD40 activation of myeloid dendritic cells. The intrahepatic immune environment is normally biased towards tolerance. Nonetheless, effective antiviral immune responses can be induced against hepatotropic pathogens. To examine the immunological basis of this paradox we studied the ability of hepatocellularly expressed hepatitis B virus (HBV) to activate immunologically naïve HBV-specific CD8⁺ T cell receptor (TCR) transgenic T cells after adoptive transfer to HBV transgenic mice. Intrahepatic priming triggered vigorous in situ T cell proliferation but failed to induce interferon gamma production or cytolytic effector function. In contrast, the same T cells differentiated into cytolytic effector T cells in HBV transgenic mice if Programmed Death 1 (PD-1) expression was genetically ablated, suggesting that intrahepatic antigen presentation per se triggers negative regulatory signals that prevent the functional differentiation of naïve CD8⁺ T cells. Surprisingly, coadministration of an agonistic anti-CD40 antibody (αCD40) inhibited PD-1 induction and restored T cell effector function, thereby inhibiting viral gene expression and causing a necroinflammatory liver disease. Importantly, the depletion of myeloid dendritic cells (mDCs) strongly diminished the αCD40 mediated functional differentiation of HBV-specific CD8⁺ T cells, suggesting that activation of mDCs was responsible for the functional differentiation of HBV-specific CD8⁺ T cells in αCD40 treated animals. These results demonstrate that antigen-specific, PD-1-mediated CD8⁺ T cell exhaustion can be rescued by CD40-mediated mDC-activation. The intrahepatic immune environment is normally biased towards tolerance. Nonetheless, effective antiviral immune responses can be induced against hepatotropic pathogens. To examine the immunological basis of this paradox we studied the ability of hepatocellularly expressed hepatitis B virus (HBV) to activate immunologically naïve HBV-specific CD8+ T cell receptor (TCR) transgenic T cells after adoptive transfer to HBV transgenic mice. Intrahepatic priming triggered vigorous in situ T cell proliferation but failed to induce interferon gamma production or cytolytic effector function. In contrast, the same T cells differentiated into cytolytic effector T cells in HBV transgenic mice if Programmed Death 1 (PD-1) expression was genetically ablated, suggesting that intrahepatic antigen presentation per se triggers negative regulatory signals that prevent the functional differentiation of naïve CD8+ T cells. Surprisingly, coadministration of an agonistic anti-CD40 antibody (αCD40) inhibited PD-1 induction and restored T cell effector function, thereby inhibiting viral gene expression and causing a necroinflammatory liver disease. Importantly, the depletion of myeloid dendritic cells (mDCs) strongly diminished the αCD40 mediated functional differentiation of HBV-specific CD8+ T cells, suggesting that activation of mDCs was responsible for the functional differentiation of HBV-specific CD8+ T cells in αCD40 treated animals. These results demonstrate that antigen-specific, PD-1-mediated CD8+ T cell exhaustion can be rescued by CD40-mediated mDC-activation. |
| Author | Kakimi, Kazuhiro Murata, Yasuhiro Chung, Josan Chisari, Francis V. Isogawa, Masanori |
| AuthorAffiliation | Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, California, United States of America Nationwide Children's Hospital, United States of America |
| AuthorAffiliation_xml | – name: Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, California, United States of America – name: Nationwide Children's Hospital, United States of America |
| Author_xml | – sequence: 1 givenname: Masanori surname: Isogawa fullname: Isogawa, Masanori – sequence: 2 givenname: Josan surname: Chung fullname: Chung, Josan – sequence: 3 givenname: Yasuhiro surname: Murata fullname: Murata, Yasuhiro – sequence: 4 givenname: Kazuhiro surname: Kakimi fullname: Kakimi, Kazuhiro – sequence: 5 givenname: Francis V. surname: Chisari fullname: Chisari, Francis V. |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/23853599$$D View this record in MEDLINE/PubMed |
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| ContentType | Journal Article |
| Copyright | 2013 Isogawa et al 2013 Isogawa et al 2013 Isogawa et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited: Isogawa M, Chung J, Murata Y, Kakimi K, Chisari FV (2013) CD40 Activation Rescues Antiviral CD8+ T Cells from PD-1-Mediated Exhaustion. PLoS Pathog 9(7): e1003490. doi:10.1371/journal.ppat.1003490 |
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| Notes | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Conceived and designed the experiments: MI FVC. Performed the experiments: MI JC YM. Analyzed the data: MI YM FVC. Contributed reagents/materials/analysis tools: MI KK FVC. Wrote the paper: MI FVC. The authors have declared that no competing interests exist. |
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| SubjectTerms | Adaptive Immunity Animals Antigen Presentation Antigens, Differentiation - genetics Antigens, Differentiation - metabolism Antigens, Viral - metabolism Biology CD40 Antigens - agonists CD40 Antigens - genetics CD40 Antigens - metabolism CD8-Positive T-Lymphocytes - immunology CD8-Positive T-Lymphocytes - metabolism CD8-Positive T-Lymphocytes - pathology CD8-Positive T-Lymphocytes - virology Cell Differentiation Cell Proliferation Dendritic Cells - immunology Dendritic Cells - metabolism Dendritic Cells - pathology Dendritic Cells - virology Gene Expression Regulation, Viral Hepatitis Hepatitis B - immunology Hepatitis B - metabolism Hepatitis B - pathology Hepatitis B - virology Hepatitis B virus - immunology Hepatitis B virus - physiology Host-Pathogen Interactions Immunology Liver Liver - immunology Liver - metabolism Liver - pathology Liver - virology Male Medical research Medicine Mice Mice, Inbred C57BL Mice, Knockout Mice, Transgenic Programmed Cell Death 1 Receptor - genetics Programmed Cell Death 1 Receptor - metabolism Receptors, Antigen, T-Cell - genetics Receptors, Antigen, T-Cell - metabolism Rodents T cell receptors T-Lymphocytes, Cytotoxic - immunology T-Lymphocytes, Cytotoxic - metabolism T-Lymphocytes, Cytotoxic - pathology T-Lymphocytes, Cytotoxic - virology |
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| Title | CD40 Activation Rescues Antiviral CD8+ T Cells from PD-1-Mediated Exhaustion |
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