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V(D)J recombination generates a diverse array of antigen-binding specificities, but breakage and re-joining of DNA segments have grave implications for the maintenance of genomic stability and oncogenic risk. Exposure of eukaryotic cells to genotoxic agents activates a DNA damage checkpoint that induces cell-cycle arrest and DNA repair, or apoptosis. We discuss several lines of evidence implicating DNA-dependent protein kinase (DNA-PK), and the gene mutated in ataxia telangiectasia (ATM), two mammalian homologues of yeast DNA damage-checkpoint genes, in regulating the response to intrinsic DNA damage that occurs during V(D)J recombination.

We have analyzed the phenotype and functional capabilities of adult and fetal CD4 8 thymocytes after 4 d of culture in IL-4 and PMA. Both adult and day 14 fetal CD4 8 thymocytes failed to acquire CD4 or CD8 antigens following culture. However, changes in expression of other antigens typical of immature thymocytes were observed. For example, the frequency with which cells expressed high levels of J11d or IL-2-R was greatly decreased following culture, whereas the frequency with which high levels of MEL-14, the lymph node homing receptor were expressed were greatly increased. This phenomenon may be due to direct induction by IL-4 and PMA of MEL-14 expression on purified MEL-14lo CD4-8- thymocytes. The frequency of cells expressing CD3, Ly-1 and Pgp-1 changed only slightly. Functionally, the cultured cells produced large amounts of interferon gamma but very little IL-2 or IL-4, although freshly isolated CD4-8- thymocytes produced all three lymphokines. These results suggest that in addition to a proliferative stimulus, culture in IL-4/PMA alters the expression of several early thymocyte antigens, the functional capabilities of CD4-8- progenitor thymocytes, and may act as a selective differentiation stimulus to MEL-14lo CD4-8- thymocytes.