Oncogenic potential of a pre-T cell receptor lacking the TCR beta variable domain.
In transgenic mice expressing a mutated T cell receptor (TCR) beta chain lacking the variable domain (DeltaV-TCRbeta) T cell differentiation is arrested at the CD4+ CD8+ thymocyte stage. Here, we report that these transgenic animals develop CD4+, CD8+, IL-2 receptor alpha-positive T cell lymphomas at a very high incidence. Introduction of a normal TCRbeta gene into the DeltaV-TCRbeta transgenic mice drastically reduces the tumor incidence, while crossing the DeltaV-TCRbeta transgene onto a recombinase-deficient RAG-1-/- background does not prevent tumor development. Therefore, the induction of T cell lymphomas is a property of the mutated TCRbeta chain. The DeltaV-TCRbeta chain appears at the cell surface as a disulfide-linked DeltaV-TCRbeta/pTalpha dimer in association with CD3gamma and -episilon, but not with CD3delta. This mutated preTCR/CD3 complex is shown to induce pre-T cell proliferation and differentiation, but does not permit formation of a normally sized CD4+8+ thymic compartment. DeltaV-TCRbeta transgenic mice frequently show an expansion of CD4+8+, IL-2 receptor alpha+ pre-T cells early in life. These cells likely represent the population that is subject to oncogenic transformation.
Jacobs
H
H
Division of Molecular Genetics, The Netherlands Cancer Institute, Amsterdam.
Ossendorp
F
F
de Vries
E
E
Ungewiss
K
K
von Boehmer
H
H
Borst
J
J
Berns
A
A
D000595:Amino Acid Sequence; D000818:Animals; D017252:CD3 Complex / Q000096:biosynthesis; D015704:CD4 Antigens / Q000096:biosynthesis; D016827:CD8 Antigens / Q000096:biosynthesis; D002454:Cell Differentiation / Q000502:physiology; D004254:DNA Nucleotidyltransferases / Q000378:metabolism; D005260:Female; D007135:Immunoglobulin Variable Region / Q000737:chemistry* / Q000235:genetics*; D019426:Integrases; D016399:Lymphoma, T-Cell / Q000235:genetics* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009154:Mutation; D009857:Oncogenes; D017434:Protein Structure, Tertiary; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics*; D045522:Recombinases; D013601:T-Lymphocytes / Q000166:cytology / Q000378:metabolism; D013950:Thymus Gland / Q000166:cytology; D019076:Transgenes
D017252:CD3 Complex; D015704:CD4 Antigens; D016827:CD8 Antigens; D007135:Immunoglobulin Variable Region; D016693:Receptors, Antigen, T-Cell, alpha-beta; D045522:Recombinases; D004254:DNA Nucleotidyltransferases; D019426:Integrases; C115006:integron integrase IntI1