BIASED T-CELL RECEPTOR-DELTA ELEMENT RECOMBINATION IN SCID THYMOCYTES

Thymocytes in mutant mice with severe combined immunodeficiency (scid thymocytes) show ongoing recombination of some T-cell receptor delta g ene elements, generating signal joints quantitatively and qualitativel y indistinguishable from those in wild-type fetal thymocytes. Excised Ddelta2-Jdelta1 and Ddelta1-Ddelta2 rearrangements are detectable at l evels equivalent to or greater than those in thymocytes from wild-type mice on fetal day 15. Signal junctional modification, shown here to o ccur frequently in wild-type adult but not newborn excised Ddelta2-Jde lta1 junctions, can occur normally in adult scid thymocytes. Excised D delta1-Ddelta2 scid junctions, similar to wild-type thymocytes, includ e pseudonormal coding junctions as well as signal junctions. Inversion al Ddelta-Ddelta2 rearrangements, generating conventional hybrid junct ions, are also reproducibly detectable in scid thymus DNA. These hybri ds, unlike those reported for artificial recombination constructs, do not show extensive nucleotide loss. In contrast to the normal or high incidences of Ddelta1-, Ddelta2-, and Jdelta-associated signal junctio ns in scid thymocytes, Vdelta1, Vgamma3, and Vgamma1.2 signal products are undetectable in scid thymocytes or are detectable at levels at le ast 10-fold lower than the levels in wild-type fetal thymocytes. These findings confirm biased T-cell receptor element recombination by V(D) J recombinase activity of nontransformed scid thymocytes and indicate that analysis of in vivo-mediated gene rearrangements is important for full understanding of how the scid mutation arrests lymphocyte develo pment.