SUBLETHAL GAMMA-RADIATION INDUCES DIFFERENTIATION OF CD4- CD8- INTO CD4+/CD8+ THYMOCYTES WITHOUT T-CELL RECEPTOR-BETA REARRANGEMENT IN RECOMBINASE ACTIVATION GENE 2-/- MICE/

DNA recombination of the immunoglobulin (Ig) or T cell receptor (TCR) gene loci is an essential step in the production of lymphocytes bearin g antigen-specific receptors. Mice that lack the ability to rearrange their Ig and TCR gene loci are devoid of mature B and T cells. Complet e rearrangement and expression of the TCR-beta chain has been suggeste d to allow immature thymocytes to switch from the CD4(-)/CD8(-) to the CD4(+)/CD8(+) stage of thymic development. Thus, thymocytes from seve re combined immune deficient (SCID) mice or mice deficient in recombin ase activation genes (RAG), which do not undergo proper DNA rearrangem ent, are arrested at the early CD4(-)/CD8(-) stage of development. B c ell precursors in SCID or RAG mice do not progress from the B220(+)/sI gM(-)/heat stable antigen (HSA)(+)/CD43(+) to the B220(+)/sIgM(-)/HSA( +)/ CD43(-) stage. In an attempt to reconstitute RAG-2-/- mice with bo ne marrow- or fetal liver-derived progenitor cells, we subjected these mice to sublethal doses of gamma-radiation. It is surprising that in the absence of donor cells, irradiated RAG-2-/- mice revealed a dramat ic change in their lymphoid phenotype. 14 d after irradiation, the maj ority of thymocytes had advanced to the CD4(+)/CD8(+) stage of T cell development and a small number of bone marrow precursors had progresse d to the CD43(-), HSA(hi) stage of B cell development. Analysis of the resulting CD4(+)/CD8(+) thymocytes revealed no surface expression of the TCR/CD3 complex and no V-D-J rearrangement of the TCR-beta gene lo cus. Our findings provide evidence for a novel pathway that allows the transition of thymocytes from the CD4(-)/CD8(-) to the CD4(+)/CD8(+) stage and that does not appear to require TCR-beta chain rearrangement .