Transnuclear mice with pre-defined T cell receptor specificities against Toxoplasma gondii obtained via SCNT.
Lymphocytes, such as T cells, undergo genetic V(D)J recombination, to generate a receptor with a certain specificity. Mice transgenic for a rearranged antigen-specific T cell receptor (TCR) have been an indispensable tool to study T cell development and function. However, such TCRs are usually isolated from the relevant T cells after long-term culture often following repeated antigen stimulation, which unavoidably selects for T cells with high affinity. Random genomic integration of the TCR α- and β-chain and expression from non-endogenous promoters can lead to variations in expression level and kinetics. Epigenetic reprogramming via somatic cell nuclear transfer provides a tool to generate embryonic stem cells and mice from any cell of interest. Consequently, when SCNT is applied to T cells of known specificity, these genetic V(D)J rearrangements are transferred to the SCNT-embryonic stem cells (ESCs) and the mice derived from them, while epigenetic marks are reset. We have demonstrated that T cells with pre-defined specificities against Toxoplasma gondii can be used to generate mouse models that express the specific TCR from their endogenous loci, without experimentally introduced genetic modification. The relative ease and speed with which such transnuclear models can be obtained holds promise for the construction of other disease models.
Kirak
Oktay
O
Whitehead Institute for Biomedical Research, USA. kirak@wi.mit.edu
Frickel
Eva-Maria
EM
Grotenbreg
Gijsbert M
GM
Suh
Heikyung
H
Jaenisch
Rudolf
R
Ploegh
Hidde L
HL
D000818:Animals; D053595:Embryonic Stem Cells / Q000276:immunology*; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D005260:Female; D051379:Mice; D053652:Nuclear Transfer Techniques; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*; D014122:Toxoplasma / Q000276:immunology*
D018984:Epitopes, T-Lymphocyte; D011948:Receptors, Antigen, T-Cell