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Nat Commun. 2017 Oct 18;8(1):1028. doi: 10.1038/s41467-017-01022-4.

DNA-binding of the Tet-transactivator curtails antigen-induced lymphocyte activation in mice.

Author information

1
Division of Developmental Immunology, Biocenter, Medical University of Innsbruck, Innrain 80, 6020, Innsbruck, Austria. Eleonora.Ottina@crick.ac.uk.
2
The Walter and Eliza Hall Institute for Medical Research, 1G Royal Parade, Victoria, 3052, Australia. Eleonora.Ottina@crick.ac.uk.
3
Retroviral Immunology, The Francis Crick Institute, 1 Midland Road, London, NW1 1AT, UK. Eleonora.Ottina@crick.ac.uk.
4
The Walter and Eliza Hall Institute for Medical Research, 1G Royal Parade, Victoria, 3052, Australia.
5
Department of Medical Biology, The University of Melbourne, Parkville, Victoria, 3050, Australia.
6
Laboratory of Translational Immunology (LTI), Utrecht (UMCU), Heidelberglaan 100, 3584 CX, Utrecht, The Netherlands.
7
Division of Developmental Immunology, Biocenter, Medical University of Innsbruck, Innrain 80, 6020, Innsbruck, Austria.
8
Division of Experimental Pathophysiology and Immunology, Biocenter, Medical University of Innsbruck, Innrain 80, 6020, Innsbruck, Austria.
9
Division of Developmental Immunology, Biocenter, Medical University of Innsbruck, Innrain 80, 6020, Innsbruck, Austria. andreas.villunger@i-med.ac.at.
10
The Tyrolean Cancer Research Institute, Innrain 66, 6020, Innsbruck, Austria. andreas.villunger@i-med.ac.at.

Abstract

The Tet-On/Off system for conditional transgene expression constitutes state-of-the-art technology to study gene function by facilitating inducible expression in a timed and reversible manner. Several studies documented the suitability and versatility of this system to trace lymphocyte fate and to conditionally express oncogenes or silence tumour suppressor genes in vivo. Here, we show that expression of the tetracycline/doxycycline-controlled Tet-transactivator, while tolerated well during development and in immunologically unchallenged animals, impairs the expansion of antigen-stimulated T and B cells and thereby curtails adaptive immune responses in vivo. Transactivator-mediated cytotoxicity depends on DNA binding, but can be overcome by BCL2 overexpression, suggesting that apoptosis induction upon lymphocyte activation limits cellular and humoral immune responses. Our findings suggest a possible system-intrinsic biological bias of the Tet-On/Off system in vivo that will favour the outgrowth of apoptosis resistant clones, thus possibly confounding data published using such systems.

PMID:
29044097
PMCID:
PMC5647323
DOI:
10.1038/s41467-017-01022-4
[Indexed for MEDLINE]
Free PMC Article

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