TY  - JOUR
U1  - Wissenschaftlicher Artikel
A1  - Theobald, Sebastian J.
A1  - Khailaie, Sahamoddin
A1  - Meyer-Hermann, Michael
A1  - Volk, Valery
A1  - Olbrich, Henning
A1  - Danisch, Simon
A1  - Gerasch, Laura
A1  - Schneider, Andreas
A1  - Sinzger, Christian
A1  - Schaudien, Dirk
A1  - Lienenklaus, Stefan
A1  - Riese, Peggy
A1  - Guzman, Carlos A.
A1  - Figueiredo, Constanca
A1  - von Kaisenberg, Constantin
A1  - Spineli, Loukia M.
A1  - Glaesener, Stephanie
A1  - Meyer-Bahlburg, Almut
A1  - Ganser, Arnold
A1  - Schmitt, Michael
A1  - Mach, Michael
A1  - Messerle, Martin
A1  - Stripecke, Renata
T1  - 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
N2  - 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.
KW  - -
KW  - HCMV
KW  - reactivation
KW  - humanized mice
KW  - T cell maturation
KW  - B cell class switch
KW  - optical imaging analyses
KW  - principal component analyses
KW  - linear discriminant analyses
Y1  - 2018
UN  - https://nbn-resolving.org/urn:nbn:de:gbv:9-opus-29656
SN  - 1664-3224
SS  - 1664-3224
U6  - https://doi.org/10.3389/fimmu.2018.02734
DO  - https://doi.org/10.3389/fimmu.2018.02734
VL  - 9
PB  - Frontiers Media S.A.
ER  -