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A transgenic dual-luciferase reporter mouse for longitudinal and functional monitoring of T cells in vivo

Item Type:Article
Title:A transgenic dual-luciferase reporter mouse for longitudinal and functional monitoring of T cells in vivo
Creators Name:Szyska, M. and Herda, S. and Althoff, S. and Heimann, A. and Russ, J. and D'Abundo, D. and Dang, T.M. and Durieux, I. and Dörken, B. and Blankenstein, T. and Na, I.K.
Abstract:Adoptive T-cell therapy (ATT) efficacy is limited when targeting large solid tumors. The evaluation of ATT outcomes using accessory treatment would greatly benefit from an in vivo monitoring tool, allowing the detection of functional parameters of transferred T cells. Here, we generated transgenic bioluminescence imaging of T cells (BLITC) mice expressing an NFAT-dependent click-beetle luciferase and a constitutive Renilla luciferase, which supports concomitant in vivo analysis of migration and activation of T cells. Rapid transferability of our system to preestablished tumor models was demonstrated in the SV40-large T antigen model via both crossbreeding of BLITC mice into a T-cell receptor (TCR)-transgenic background and TCR transduction of BLITC T cells. We observed rapid tumor infiltration of BLITC CD8(+) T cells followed by a burst-like activation that mirrored rejection kinetics. Using the BLITC reporter in the clinically relevant H-Y model, we performed female to male transfers and detected H-Y-specific alloreactivity (graft-versus-host disease) in vivo In an H-Y solid tumor model, we found migration of adoptively transferred H-Y TCR-transgenic CD4(+) T cells into the tumor, marked by transient activation. This suggests a rapid inactivation of infiltrating T cells by the tumor microenvironment, as confirmed by their expression of inhibitory receptors. In summary, the BLITC reporter system facilitates analysis of therapeutic parameters for ATT, is rapidly transferable to models of interest not restricted to tumor research, and is suitable for rapid screening of TCR clones for tumor rejection kinetics, as well as off-target effects.
Keywords:Animal Disease Models, Bone Marrow Transplantation, Cell Tracking, Gene Expression, Gene Order, Genetic Transduction, Genetic Vectors, Graft vs Host Disease, Knockout Mice, Luciferases, Lymphocyte Activation, Recurrence, Reporter Genes, T-Lymphocytes, Transgenic Mice, Tumor-Infiltrating Lymphocytes, Xenograft Model Antitumor Assays, Animals, Mice
Source:Cancer Immunology Research
Publisher:American Association for Cancer Research
Page Range:110-120
Date:January 2018
Official Publication:https://doi.org/10.1158/2326-6066.CIR-17-0256
PubMed:View item in PubMed

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