Effector memory CD8 T cell response elicits Hepatitis E Virus genotype 3 pathogenesis in the elderly
Genotype 3 Hepatitis E virus (HEV-3) is an emerging threat for aging population. More than one third of older infected patients develops clinical symptoms with severe liver damage, while others remain asymptomatic. The origin of this discrepancy is still elusive although HEV-3 pathogenesis appears t...
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| Published in | PLoS pathogens Vol. 17; no. 2; p. e1009367 |
|---|---|
| Main Authors | , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
United States
Public Library of Science
01.02.2021
Public Library of Science (PLoS) |
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| Online Access | Get full text |
| ISSN | 1553-7374 1553-7366 1553-7374 |
| DOI | 10.1371/journal.ppat.1009367 |
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| Abstract | Genotype 3 Hepatitis E virus (HEV-3) is an emerging threat for aging population. More than one third of older infected patients develops clinical symptoms with severe liver damage, while others remain asymptomatic. The origin of this discrepancy is still elusive although HEV-3 pathogenesis appears to be immune-mediated. Therefore, we investigated the role of CD8 T cells in the outcome of the infection in immunocompetent elderly subjects. We enrolled twenty two HEV-3-infected patients displaying similar viral determinants and fifteen healthy donors. Among the infected group, sixteen patients experienced clinical symptoms related to liver disease while six remained asymptomatic. Here we report that symptomatic infection is characterized by an expansion of highly activated effector memory CD8 T (EM) cells, regardless of antigen specificity. This robust activation is associated with key features of early T cell exhaustion including a loss in polyfunctional type-1 cytokine production and partial commitment to type-2 cells. In addition, we show that bystander activation of EM cells seems to be dependent on the inflammatory cytokines IL-15 and IL-18, and is supported by an upregulation of the activating receptor NKG2D and an exuberant expression of T-Bet and T-Bet-regulated genes including granzyme B and CXCR3. We also show that the inflammatory chemokines CXCL9-10 are increased in symptomatic patients thereby fostering the recruitment of highly cytotoxic EM cells into the liver in a CXCR3-dependent manner. Finally, we find that the EM-biased immune response returns to homeostasis following viral clearance and disease resolution, further linking the EM cells response to viral burden. Conversely, asymptomatic patients are endowed with low-to-moderate EM cell response. In summary, our findings define immune correlates that contribute to HEV-3 pathogenesis and emphasize the central role of EM cells in governing the outcome of the infection. |
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| AbstractList | Genotype 3 Hepatitis E virus (HEV-3) is an emerging threat for aging population. More than one third of older infected patients develops clinical symptoms with severe liver damage, while others remain asymptomatic. The origin of this discrepancy is still elusive although HEV-3 pathogenesis appears to be immune-mediated. Therefore, we investigated the role of CD8 T cells in the outcome of the infection in immunocompetent elderly subjects. We enrolled twenty two HEV-3-infected patients displaying similar viral determinants and fifteen healthy donors. Among the infected group, sixteen patients experienced clinical symptoms related to liver disease while six remained asymptomatic. Here we report that symptomatic infection is characterized by an expansion of highly activated effector memory CD8 T (EM) cells, regardless of antigen specificity. This robust activation is associated with key features of early T cell exhaustion including a loss in polyfunctional type-1 cytokine production and partial commitment to type-2 cells. In addition, we show that bystander activation of EM cells seems to be dependent on the inflammatory cytokines IL-15 and IL-18, and is supported by an upregulation of the activating receptor NKG2D and an exuberant expression of T-Bet and T-Bet-regulated genes including granzyme B and CXCR3. We also show that the inflammatory chemokines CXCL9-10 are increased in symptomatic patients thereby fostering the recruitment of highly cytotoxic EM cells into the liver in a CXCR3-dependent manner. Finally, we find that the EM-biased immune response returns to homeostasis following viral clearance and disease resolution, further linking the EM cells response to viral burden. Conversely, asymptomatic patients are endowed with low-to-moderate EM cell response. In summary, our findings define immune correlates that contribute to HEV-3 pathogenesis and emphasize the central role of EM cells in governing the outcome of the infection. [...]the CD45RA+CCR7+ are naïve (N), the CD45RA+CCR7- are effectors (E), the CD45RA-CCR7+ are central memory (CM) and the CD45RA-CCR7- are effector memory (EM) cells. [...]the frequency of the EM subset was significantly increased in symptomatic patients (Fig 1B and 1C). [...]drastic phenotypic changes were specifically observed within the EM compartment (Figs 1D and S1A). [...]to visualize the global pattern of EM subsets during the acute phase of the infection, we included all the aforementioned markers in a principal component analysis (Fig 1F). Symptomatic patients (S, red), asymptomatic patients (AS, black) and healthy controls (C, white). https://doi.org/10.1371/journal.ppat.1009367.g001 Coordinated expression of HLA-DR, CD38 and PD-1 discriminates symptomatic HEV-3 infection in the elderly HLA-DR, CD38 and PD-1 expression displayed the highest impact on the principal component 1 (PC1) when compared to the other principal component analysis loadings (Fig 1F). Since phenotypic changes in the EM compartment are correlated with the activation status, we focused our analysis on HLA-DR, CD38 and PD-1 as representative markers to provide a concise immune signature discriminating symptomatic from asymptomatic patients. [...]the CD45RA+CCR7+ are naïve (N), the CD45RA+CCR7- are effectors (E), the CD45RA-CCR7+ are central memory (CM) and the CD45RA-CCR7- are effector memory (EM) cells. [...]the frequency of the EM subset was significantly increased in symptomatic patients (Fig 1B and 1C). [...]drastic phenotypic changes were specifically observed within the EM compartment (Figs 1D and S1A). [...]to visualize the global pattern of EM subsets during the acute phase of the infection, we included all the aforementioned markers in a principal component analysis (Fig 1F). Symptomatic patients (S, red), asymptomatic patients (AS, black) and healthy controls (C, white). https://doi.org/10.1371/journal.ppat.1009367.g001 Coordinated expression of HLA-DR, CD38 and PD-1 discriminates symptomatic HEV-3 infection in the elderly HLA-DR, CD38 and PD-1 expression displayed the highest impact on the principal component 1 (PC1) when compared to the other principal component analysis loadings (Fig 1F). Since phenotypic changes in the EM compartment are correlated with the activation status, we focused our analysis on HLA-DR, CD38 and PD-1 as representative markers to provide a concise immune signature discriminating symptomatic from asymptomatic patients. Genotype 3 Hepatitis E virus (HEV-3) is an emerging threat for aging population. More than one third of older infected patients develops clinical symptoms with severe liver damage, while others remain asymptomatic. The origin of this discrepancy is still elusive although HEV-3 pathogenesis appears to be immune-mediated. Therefore, we investigated the role of CD8 T cells in the outcome of the infection in immunocompetent elderly subjects. We enrolled twenty two HEV-3-infected patients displaying similar viral determinants and fifteen healthy donors. Among the infected group, sixteen patients experienced clinical symptoms related to liver disease while six remained asymptomatic. Here we report that symptomatic infection is characterized by an expansion of highly activated effector memory CD8 T (EM) cells, regardless of antigen specificity. This robust activation is associated with key features of early T cell exhaustion including a loss in polyfunctional type-1 cytokine production and partial commitment to type-2 cells. In addition, we show that bystander activation of EM cells seems to be dependent on the inflammatory cytokines IL-15 and IL-18, and is supported by an upregulation of the activating receptor NKG2D and an exuberant expression of T-Bet and T-Bet-regulated genes including granzyme B and CXCR3. We also show that the inflammatory chemokines CXCL9-10 are increased in symptomatic patients thereby fostering the recruitment of highly cytotoxic EM cells into the liver in a CXCR3-dependent manner. Finally, we find that the EM-biased immune response returns to homeostasis following viral clearance and disease resolution, further linking the EM cells response to viral burden. Conversely, asymptomatic patients are endowed with low-to-moderate EM cell response. In summary, our findings define immune correlates that contribute to HEV-3 pathogenesis and emphasize the central role of EM cells in governing the outcome of the infection.Genotype 3 Hepatitis E virus (HEV-3) is an emerging threat for aging population. More than one third of older infected patients develops clinical symptoms with severe liver damage, while others remain asymptomatic. The origin of this discrepancy is still elusive although HEV-3 pathogenesis appears to be immune-mediated. Therefore, we investigated the role of CD8 T cells in the outcome of the infection in immunocompetent elderly subjects. We enrolled twenty two HEV-3-infected patients displaying similar viral determinants and fifteen healthy donors. Among the infected group, sixteen patients experienced clinical symptoms related to liver disease while six remained asymptomatic. Here we report that symptomatic infection is characterized by an expansion of highly activated effector memory CD8 T (EM) cells, regardless of antigen specificity. This robust activation is associated with key features of early T cell exhaustion including a loss in polyfunctional type-1 cytokine production and partial commitment to type-2 cells. In addition, we show that bystander activation of EM cells seems to be dependent on the inflammatory cytokines IL-15 and IL-18, and is supported by an upregulation of the activating receptor NKG2D and an exuberant expression of T-Bet and T-Bet-regulated genes including granzyme B and CXCR3. We also show that the inflammatory chemokines CXCL9-10 are increased in symptomatic patients thereby fostering the recruitment of highly cytotoxic EM cells into the liver in a CXCR3-dependent manner. Finally, we find that the EM-biased immune response returns to homeostasis following viral clearance and disease resolution, further linking the EM cells response to viral burden. Conversely, asymptomatic patients are endowed with low-to-moderate EM cell response. In summary, our findings define immune correlates that contribute to HEV-3 pathogenesis and emphasize the central role of EM cells in governing the outcome of the infection. Genotype 3 Hepatitis E virus (HEV-3) is an emerging threat for aging population. More than one third of older infected patients develops clinical symptoms with severe liver damage, while others remain asymptomatic. The origin of this discrepancy is still elusive although HEV-3 pathogenesis appears to be immune-mediated. Therefore, we investigated the role of CD8 T cells in the outcome of the infection in immunocompetent elderly subjects. We enrolled twenty two HEV-3-infected patients displaying similar viral determinants and fifteen healthy donors. Among the infected group, sixteen patients experienced clinical symptoms related to liver disease while six remained asymptomatic. Here we report that symptomatic infection is characterized by an expansion of highly activated effector memory CD8 T (EM) cells, regardless of antigen specificity. This robust activation is associated with key features of early T cell exhaustion including a loss in polyfunctional type-1 cytokine production and partial commitment to type-2 cells. In addition, we show that bystander activation of EM cells seems to be dependent on the inflammatory cytokines IL-15 and IL-18, and is supported by an upregulation of the activating receptor NKG2D and an exuberant expression of T-Bet and T-Bet-regulated genes including granzyme B and CXCR3. We also show that the inflammatory chemokines CXCL9-10 are increased in symptomatic patients thereby fostering the recruitment of highly cytotoxic EM cells into the liver in a CXCR3-dependent manner. Finally, we find that the EM-biased immune response returns to homeostasis following viral clearance and disease resolution, further linking the EM cells response to viral burden. Conversely, asymptomatic patients are endowed with low-to-moderate EM cell response. In summary, our findings define immune correlates that contribute to HEV-3 pathogenesis and emphasize the central role of EM cells in governing the outcome of the infection. The outcome of Genotype 3 Hepatitis E virus (HEV-3) infection differs among the elderly. Some patients develop severe forms of Hepatitis E while others remain asymptomatic. Nonetheless, parameters which can lead to severe versus silent infection are largely unknown. Therefore, we investigated immunological features of CD8 T cells in infected patients (aged ≥55) with similar viral determinants but distinct clinical outcomes. We show that drastic phenotypic changes were specifically observed within the effector memory (EM) compartment. Compared to asymptomatic patients, symptomatic ones display a strong activation of both HEV-3-specific and -nonspecific EM CD8 T cells associated with qualitative and quantitative alterations in cytokine production. In addition, EM cells are endowed with high cytotoxic capacity and have the ability to rapidly migrate to the liver. Finally, we report that the inflammatory response to HEV-3 infection shape EM cell activation and function in symptomatic elderly patients. In summary, our results present the first report demonstrating that the nature and the magnitude of EM CD8 T cell response play an important role in the outcome of HEV-3 infection in the elderly. |
| Author | Kamar, Nassim Abravanel, Florence Bahraoui, Elmostafa Izopet, Jacques Peron, Jean-Marie Gouilly, Jordi Jabrane-Ferrat, Nabila El Costa, Hicham |
| AuthorAffiliation | 3 Département de Gastroentérologie, CHU Toulouse, Toulouse, France 1 Infinity—Université Toulouse, CNRS, Inserm, Toulouse, France 2 Laboratoire de Virologie, Centre National de référence HEV, Institut Fédératif de Biologie, CHU Toulouse, Toulouse, France Nationwide Children’s Hospital, UNITED STATES |
| AuthorAffiliation_xml | – name: 3 Département de Gastroentérologie, CHU Toulouse, Toulouse, France – name: 2 Laboratoire de Virologie, Centre National de référence HEV, Institut Fédératif de Biologie, CHU Toulouse, Toulouse, France – name: 1 Infinity—Université Toulouse, CNRS, Inserm, Toulouse, France – name: Nationwide Children’s Hospital, UNITED STATES |
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| Copyright | 2021 El Costa et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License. Distributed under a Creative Commons Attribution 4.0 International License 2021 El Costa et al 2021 El Costa et al |
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| Snippet | Genotype 3 Hepatitis E virus (HEV-3) is an emerging threat for aging population. More than one third of older infected patients develops clinical symptoms with... [...]the CD45RA+CCR7+ are naïve (N), the CD45RA+CCR7- are effectors (E), the CD45RA-CCR7+ are central memory (CM) and the CD45RA-CCR7- are effector memory (EM)... |
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| SubjectTerms | Adaptive immunology Aged Antigens Asymptomatic Biology and life sciences Case-Control Studies CCR7 protein CD38 antigen CD45RA antigen CD8 antigen CD8-Positive T-Lymphocytes / immunology Computer and Information Sciences Cytokines Cytokines / metabolism Cytotoxicity Effector cells epatitis E / pathology Genotype Genotype & phenotype Genotypes Hepatitis Hepatitis E / immunology Hepatitis E virus / classification Hepatitis E virus / genetics Histocompatibility antigen HLA Human health and pathology Hépatology and Gastroenterology Immune response Immunologic Memory / immunology Immunological memory Immunology Infections Infectious diseases Life Sciences Liver diseases Lymphocytes Lymphocytes T Markers Medicine and health sciences Memory cells Older people Pathogenesis PD-1 protein Principal components analysis Receptors, CXCR3 / metabolism Research and Analysis Methods Tumor necrosis factor-TNF Viruses |
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| Title | Effector memory CD8 T cell response elicits Hepatitis E Virus genotype 3 pathogenesis in the elderly |
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