DEVELOPMENT OF CD4(-DEFICIENT MICE THROUGH A T-CELL RECEPTOR-BETA CHAIN-INDEPENDENT PATHWAY()CD8(+) THYMOCYTES IN RAG)

Antigen-binding diversity is generated by site-specific V(D)J recombin ation of the T cell receptor (TCR) and immunoglobulin loci in lymphocy te precursors. Coordinate expression of two structurally distinct reco mbinase activating genes, RAG-1 and RAG-2, is necessary for activation of site-specific V(D)J recombination. In mice bearing targeted disrup tions of either the RAG-1 or RAG-2 genes, T and B lymphocyte developme nt is arrested at the CD4-8- double negative (DN) thymocyte or B220(+) /CD43(+) pro-B cell stage. Development of CD4(+)CD8(+) double positive (DP) thymocytes is restored by expression of a functionally rearrange d TCR beta transgene, suggesting that TCR beta expression is critical for this developmental transition. We have found that treatment of adu lt or newborn RAG-deficient mice with a single sublethal dose of gamma -irradiation rescues the DN to DP transition in early thymocytes, and this is accompanied by a dramatic increase in thymus cellularity. In c ontrast to the observed induction of thymocyte maturation, there was n o phenotypic or functional evidence of coincident B lymphocyte develop ment in irradiated RAG-deficient mice. Interestingly, maturation of DP thymocytes occurred without expression of TCR beta protein in the cyt oplasm or on the cell surface. These results suggest an in vivo pathwa y for DP thymocyte development which is TCR beta chain independent.