DNA-binding of the Tet-transactivator Curtails Antigen-induced Lymphocyte Activation in Mice

Overview

Journal Nat Commun

Specialty Biology

Date 2017 Oct 19

PMID 29044097

Citations 4

Authors

Eleonora Ottina

Victor Peperzak

Katia Schoeler

Emma Carrington

Roswitha Sgonc

Marc Pellegrini

Simon Preston

Marco J Herold

Andreas Strasser

Andreas Villunger

Affiliations

Soon will be listed here.

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.

Citing Articles

Tetracycline response element driven Cre causes ectopic recombinase activity independent of transactivator element.

Lewis K, Oles L, MacDougald O Mol Metab. 2022; 61:101501.

PMID: 35452876 PMC: 9170755. DOI: 10.1016/j.molmet.2022.101501.

The Tetracycline-Controlled Transactivator (Tet-On/Off) System in β-Cells Reduces Insulin Expression and Secretion in Mice.

Jouvet N, Bouyakdan K, Campbell S, Baldwin C, Townsend S, Gannon M Diabetes. 2021; 70(12):2850-2859.

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Immune Relevant and Immune Deficient Mice: Options and Opportunities in Translational Research.

Radaelli E, Santagostino S, Sellers R, Brayton C ILAR J. 2019; 59(3):211-246.

PMID: 31197363 PMC: 7114723. DOI: 10.1093/ilar/ily026.

Correspondence: T cells are compromised in tetracycline transactivator transgenic mice.

Schmitt A, Schulze-Osthoff K, Hailfinger S Cell Death Differ. 2018; 25(3):634-636.

PMID: 29352266 PMC: 5864203. DOI: 10.1038/s41418-017-0042-y.

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