Signatures of T and B Cell Development, Functional Responses and PD-1 Upregulation After HCMV Latent Infections and Reactivations in Nod.Rag.Gamma Mice Humanized With Cord Blood CD34+ Cells
Human cytomegalovirus (HCMV) latency is typically harmless but reactivation can be largely detrimental to immune compromised hosts. We modeled latency and reactivation using a traceable HCMV laboratory strain expressing the Gaussia luciferase reporter gene (HCMV/GLuc) in order to interrogate the vir...
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| Language: | English |
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Frontiers Media S.A.
2018-11-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fimmu.2018.02734/full |
| _version_ | 1811233242024509440 |
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| author | Sebastian J. Theobald Sebastian J. Theobald Sebastian J. Theobald Sahamoddin Khailaie Michael Meyer-Hermann Michael Meyer-Hermann Valery Volk Valery Volk Henning Olbrich Henning Olbrich Henning Olbrich Simon Danisch Simon Danisch Simon Danisch Laura Gerasch Laura Gerasch Andreas Schneider Andreas Schneider Christian Sinzger Dirk Schaudien Stefan Lienenklaus Peggy Riese Carlos A. Guzman Constanca Figueiredo Constantin von Kaisenberg Loukia M. Spineli Stephanie Glaesener Almut Meyer-Bahlburg Arnold Ganser Michael Schmitt Michael Mach Martin Messerle Martin Messerle Renata Stripecke Renata Stripecke Renata Stripecke |
| author_facet | Sebastian J. Theobald Sebastian J. Theobald Sebastian J. Theobald Sahamoddin Khailaie Michael Meyer-Hermann Michael Meyer-Hermann Valery Volk Valery Volk Henning Olbrich Henning Olbrich Henning Olbrich Simon Danisch Simon Danisch Simon Danisch Laura Gerasch Laura Gerasch Andreas Schneider Andreas Schneider Christian Sinzger Dirk Schaudien Stefan Lienenklaus Peggy Riese Carlos A. Guzman Constanca Figueiredo Constantin von Kaisenberg Loukia M. Spineli Stephanie Glaesener Almut Meyer-Bahlburg Arnold Ganser Michael Schmitt Michael Mach Martin Messerle Martin Messerle Renata Stripecke Renata Stripecke Renata Stripecke |
| author_sort | Sebastian J. Theobald |
| collection | DOAJ |
| description | Human cytomegalovirus (HCMV) latency is typically harmless but reactivation can be largely detrimental to immune compromised hosts. We modeled latency and reactivation using a traceable HCMV laboratory strain expressing the Gaussia luciferase reporter gene (HCMV/GLuc) in order to interrogate the viral modulatory effects on the human adaptive immunity. Humanized mice with long-term (more than 17 weeks) steady human T and B cell immune reconstitutions were infected with HCMV/GLuc and 7 weeks later were further treated with granulocyte-colony stimulating factor (G-CSF) to induce viral reactivations. Whole body bio-luminescence imaging analyses clearly differentiated mice with latent viral infections vs. reactivations. Foci of vigorous viral reactivations were detectable in liver, lymph nodes and salivary glands. The number of viral genome copies in various tissues increased upon reactivations and were detectable in sorted human CD14+, CD169+, and CD34+ cells. Compared with non-infected controls, mice after infections and reactivations showed higher thymopoiesis, systemic expansion of Th, CTL, Treg, and Tfh cells and functional antiviral T cell responses. Latent infections promoted vast development of memory CD4+ T cells while reactivations triggered a shift toward effector T cells expressing PD-1. Further, reactivations prompted a marked development of B cells, maturation of IgG+ plasma cells, and HCMV-specific antibody responses. Multivariate statistical methods were employed using T and B cell immune phenotypic profiles obtained with cells from several tissues of individual mice. The data was used to identify combinations of markers that could predict an HCMV infection vs. reactivation status. In spleen, but not in lymph nodes, higher frequencies of effector CD4+ T cells expressing PD-1 were among the factors most suited to distinguish HCMV reactivations from infections. These results suggest a shift from a T cell dominated immune response during latent infections toward an exhausted T cell phenotype and active humoral immune response upon reactivations. In sum, this novel in vivo humanized model combined with advanced analyses highlights a dynamic system clearly specifying the immunological spatial signatures of HCMV latency and reactivations. These signatures can be merged as predictive biomarker clusters that can be applied in the clinical translation of new therapies for the control of HCMV reactivation. |
| first_indexed | 2024-04-12T11:17:42Z |
| format | Article |
| id | doaj.art-2f391d38b86f4d808225f222366bbfad |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-04-12T11:17:42Z |
| publishDate | 2018-11-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-2f391d38b86f4d808225f222366bbfad2022-12-22T03:35:27ZengFrontiers Media S.A.Frontiers in Immunology1664-32242018-11-01910.3389/fimmu.2018.02734418849Signatures of T and B Cell Development, Functional Responses and PD-1 Upregulation After HCMV Latent Infections and Reactivations in Nod.Rag.Gamma Mice Humanized With Cord Blood CD34+ CellsSebastian J. Theobald0Sebastian J. Theobald1Sebastian J. Theobald2Sahamoddin Khailaie3Michael Meyer-Hermann4Michael Meyer-Hermann5Valery Volk6Valery Volk7Henning Olbrich8Henning Olbrich9Henning Olbrich10Simon Danisch11Simon Danisch12Simon Danisch13Laura Gerasch14Laura Gerasch15Andreas Schneider16Andreas Schneider17Christian Sinzger18Dirk Schaudien19Stefan Lienenklaus20Peggy Riese21Carlos A. Guzman22Constanca Figueiredo23Constantin von Kaisenberg24Loukia M. Spineli25Stephanie Glaesener26Almut Meyer-Bahlburg27Arnold Ganser28Michael Schmitt29Michael Mach30Martin Messerle31Martin Messerle32Renata Stripecke33Renata Stripecke34Renata Stripecke35Clinic of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover, GermanyExcellence Cluster REBIRTH, Laboratory of Regenerative Immune Therapies Applied, Hannover Medical School, Hannover, GermanyPartner Site Hannover-Braunschweig, German Center for Infection Research (DZIF), Braunschweig, GermanyDepartment of Systems Immunology and Braunschweig Integrated Centre of Systems Biology (BRICS), Helmholtz Centre for Infection Research, Braunschweig, GermanyDepartment of Systems Immunology and Braunschweig Integrated Centre of Systems Biology (BRICS), Helmholtz Centre for Infection Research, Braunschweig, GermanyInstitute for Biochemistry, Biotechnology and Bioinformatics, Technical University Braunschweig, Braunschweig, GermanyClinic of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover, GermanyExcellence Cluster REBIRTH, Laboratory of Regenerative Immune Therapies Applied, Hannover Medical School, Hannover, GermanyClinic of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover, GermanyExcellence Cluster REBIRTH, Laboratory of Regenerative Immune Therapies Applied, Hannover Medical School, Hannover, GermanyPartner Site Hannover-Braunschweig, German Center for Infection Research (DZIF), Braunschweig, GermanyClinic of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover, GermanyExcellence Cluster REBIRTH, Laboratory of Regenerative Immune Therapies Applied, Hannover Medical School, Hannover, GermanyPartner Site Hannover-Braunschweig, German Center for Infection Research (DZIF), Braunschweig, GermanyClinic of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover, GermanyExcellence Cluster REBIRTH, Laboratory of Regenerative Immune Therapies Applied, Hannover Medical School, Hannover, GermanyClinic of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover, GermanyExcellence Cluster REBIRTH, Laboratory of Regenerative Immune Therapies Applied, Hannover Medical School, Hannover, GermanyInstitute of Virology, University of Ulm, Ulm, GermanyFraunhofer Institute for Toxicology and Experimental Medicine (ITEM), Hannover, GermanyInstitute for Laboratory Animal Science, Hannover Medical School, Hannover, GermanyDepartment of Vaccinology and Applied Microbiology, Helmholtz Centre for Infection Research Braunschweig, Braunschweig, GermanyDepartment of Vaccinology and Applied Microbiology, Helmholtz Centre for Infection Research Braunschweig, Braunschweig, Germany0Department of Transfusion Medicine, Hannover Medical School, Hannover, Germany1Clinic of Gynecology and Obstetrics, Hannover Medical School, Hannover, Germany2Institute for Biostatistics, Hannover Medical School, Hannover, GermanyClinic of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany3Department of Pediatrics, University Medicine Greifswald, Greifswald, GermanyClinic of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany4Department of Hematology, Oncology and Rheumatology, GMP Core Facility, Heidelberg University Hospital, Heidelberg, Germany5Institute of Virology, University Erlangen-Nürnberg, Erlangen, GermanyPartner Site Hannover-Braunschweig, German Center for Infection Research (DZIF), Braunschweig, Germany6Institute of Virology, Hannover Medical School, Hannover, GermanyClinic of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover, GermanyExcellence Cluster REBIRTH, Laboratory of Regenerative Immune Therapies Applied, Hannover Medical School, Hannover, GermanyPartner Site Hannover-Braunschweig, German Center for Infection Research (DZIF), Braunschweig, GermanyHuman cytomegalovirus (HCMV) latency is typically harmless but reactivation can be largely detrimental to immune compromised hosts. We modeled latency and reactivation using a traceable HCMV laboratory strain expressing the Gaussia luciferase reporter gene (HCMV/GLuc) in order to interrogate the viral modulatory effects on the human adaptive immunity. Humanized mice with long-term (more than 17 weeks) steady human T and B cell immune reconstitutions were infected with HCMV/GLuc and 7 weeks later were further treated with granulocyte-colony stimulating factor (G-CSF) to induce viral reactivations. Whole body bio-luminescence imaging analyses clearly differentiated mice with latent viral infections vs. reactivations. Foci of vigorous viral reactivations were detectable in liver, lymph nodes and salivary glands. The number of viral genome copies in various tissues increased upon reactivations and were detectable in sorted human CD14+, CD169+, and CD34+ cells. Compared with non-infected controls, mice after infections and reactivations showed higher thymopoiesis, systemic expansion of Th, CTL, Treg, and Tfh cells and functional antiviral T cell responses. Latent infections promoted vast development of memory CD4+ T cells while reactivations triggered a shift toward effector T cells expressing PD-1. Further, reactivations prompted a marked development of B cells, maturation of IgG+ plasma cells, and HCMV-specific antibody responses. Multivariate statistical methods were employed using T and B cell immune phenotypic profiles obtained with cells from several tissues of individual mice. The data was used to identify combinations of markers that could predict an HCMV infection vs. reactivation status. In spleen, but not in lymph nodes, higher frequencies of effector CD4+ T cells expressing PD-1 were among the factors most suited to distinguish HCMV reactivations from infections. These results suggest a shift from a T cell dominated immune response during latent infections toward an exhausted T cell phenotype and active humoral immune response upon reactivations. In sum, this novel in vivo humanized model combined with advanced analyses highlights a dynamic system clearly specifying the immunological spatial signatures of HCMV latency and reactivations. These signatures can be merged as predictive biomarker clusters that can be applied in the clinical translation of new therapies for the control of HCMV reactivation.https://www.frontiersin.org/article/10.3389/fimmu.2018.02734/fullHCMVreactivationhumanized miceT cell maturationB cell class switchoptical imaging analyses |
| spellingShingle | Sebastian J. Theobald Sebastian J. Theobald Sebastian J. Theobald Sahamoddin Khailaie Michael Meyer-Hermann Michael Meyer-Hermann Valery Volk Valery Volk Henning Olbrich Henning Olbrich Henning Olbrich Simon Danisch Simon Danisch Simon Danisch Laura Gerasch Laura Gerasch Andreas Schneider Andreas Schneider Christian Sinzger Dirk Schaudien Stefan Lienenklaus Peggy Riese Carlos A. Guzman Constanca Figueiredo Constantin von Kaisenberg Loukia M. Spineli Stephanie Glaesener Almut Meyer-Bahlburg Arnold Ganser Michael Schmitt Michael Mach Martin Messerle Martin Messerle Renata Stripecke Renata Stripecke Renata Stripecke Signatures of T and B Cell Development, Functional Responses and PD-1 Upregulation After HCMV Latent Infections and Reactivations in Nod.Rag.Gamma Mice Humanized With Cord Blood CD34+ Cells Frontiers in Immunology HCMV reactivation humanized mice T cell maturation B cell class switch optical imaging analyses |
| title | Signatures of T and B Cell Development, Functional Responses and PD-1 Upregulation After HCMV Latent Infections and Reactivations in Nod.Rag.Gamma Mice Humanized With Cord Blood CD34+ Cells |
| title_full | Signatures of T and B Cell Development, Functional Responses and PD-1 Upregulation After HCMV Latent Infections and Reactivations in Nod.Rag.Gamma Mice Humanized With Cord Blood CD34+ Cells |
| title_fullStr | Signatures of T and B Cell Development, Functional Responses and PD-1 Upregulation After HCMV Latent Infections and Reactivations in Nod.Rag.Gamma Mice Humanized With Cord Blood CD34+ Cells |
| title_full_unstemmed | Signatures of T and B Cell Development, Functional Responses and PD-1 Upregulation After HCMV Latent Infections and Reactivations in Nod.Rag.Gamma Mice Humanized With Cord Blood CD34+ Cells |
| title_short | Signatures of T and B Cell Development, Functional Responses and PD-1 Upregulation After HCMV Latent Infections and Reactivations in Nod.Rag.Gamma Mice Humanized With Cord Blood CD34+ Cells |
| title_sort | signatures of t and b cell development functional responses and pd 1 upregulation after hcmv latent infections and reactivations in nod rag gamma mice humanized with cord blood cd34 cells |
| topic | HCMV reactivation humanized mice T cell maturation B cell class switch optical imaging analyses |
| url | https://www.frontiersin.org/article/10.3389/fimmu.2018.02734/full |
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