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 cha in lacking the variable domain (Delta V-TCR beta) T cell differentiati on is arrested at the CD4(+) CD8(+) thymocyte stage, Here, we report t hat these transgenic animals develop CD4(+), CD8(+), IL-2 receptor alp ha-positive T cell lymphomas at a very high incidence. Introduction of a normal TCR beta gene into the Delta V-TCR beta transgenic mice dras tically reduces the tumor incidence, while crossing the Delta V-TCR be ta transgene onto a recombinase-deficient RAG-1(-/-) background does n ot prevent tumor development, Therefore, the induction of T cell lymph omas is a property of the mutated TCR beta chain, The Delta V- TCR bet a chain appears at the cell surface as a disulfide-linked Delta V-TCR beta/pT alpha dimer in association with CD3 gamma and -epsilon, but no t with CD3 delta. This mutated preTCR/CD3 complex is shown to induce p re-T cell proliferation and differentiation, but does not permit forma tion of a normally sized CD4(+)8(+) thymic compartment, Delta V-TCR be ta transgenic mice frequently show an expansion of CD4(+)8(+), IL-2 re ceptor alpha(+) pre-T cells early in life, These cells likely represen t the population that is subject to oncogenic transformation.