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Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Immunol. | doi: 10.3389/fimmu.2018.02734

Multidimensional signatures of T cell maturation, PD-1 upregulation and B cell class-switch after HCMV latent infections and reactivations in humanized mice.

  • 1Clinic of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Germany
  • 2Department of Systems Immunology, Helmholtz-Zentrum für Infektionsforschung, Helmholtz-Gemeinschaft Deutscher Forschungszentren (HZ), Germany
  • 3Institute of Virology, Universitätsklinikum Ulm, Germany
  • 4Fraunhofer-Institut für Toxikologie und Experimentelle Medizin (FHG), Germany
  • 5Department of Pediatrics, University of Greifswald, Germany
  • 6Department of Hematology, Oncology and Rheumatology, GMP Core facility, Heidelberg University Hospital, Germany
  • 7Institute of Virology, University Erlangen-Nürnberg, Friedrich-Alexander-Universität Erlangen-Nürnberg, Germany

Human cytomegalovirus (HCMV) latency is typically harmless but reactivation can be largely detrimental to immune compromised hosts. We modelled 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 seventeen weeks) steady human T and B cell immune reconstitutions were infected with HCMV/GLuc and seven 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 versus 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 towards 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 versus 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 towards 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.

Keywords: hcmv, Reactivation, humanized mice, T CELL MATURATION, B cell class switching, optical imaging analyses, Principal component analyses (PCA), Linear discriminant analyses

Received: 10 Aug 2018; Accepted: 06 Nov 2018.

Edited by:

Stipan Jonjic, University of Rijeka, Croatia

Reviewed by:

Christopher M. Snyder, Thomas Jefferson University, United States
Udo F. Hartwig, Department of Internal Medicine III, University Medical Centre, Johannes Gutenberg University Mainz, Germany  

Copyright: © 2018 Theobald, Khailaie, Meyer-Hermann, Volk, Olbrich, Danisch, Gerasch, Schneider, Sinzger, Schaudien, Lienenklaus, Riese, Guzmán, Figueiredo, Kaisenberg, Spineli, Glaesener, Meyer-Bahlburg, Ganser, Schmitt, Mach, Messerle and Stripecke. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Prof. Renata Stripecke, Hannover Medical School, Clinic of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hanover, 30625, Lower Saxony, Germany, Stripecke.Renata@mh-hannover.de