The role of IL-7 in early T cell development has been studied. It had been shown by our collaborators that knockout of IL-7 receptor severely impairs T cell development but the nature of these critical IL-7 activities have not been defined. We observe that the two major types of T cells, alpha-beta vs gamma-delta, have different IL-7 requirements. alpha-beta T cells require IL-7 for optimal viability during two early precursor stages, CD25- and CD25+. In the absence of IL-7, severe loss of these cells occurs via apoptosis and this loss can be reversed by a bcl-2 transgene (and in preliminary experiments by inhibitors of ICE), restoring alpha-beta T cell development. gamma- delta T cells require IL-7 for an additional process, rearrangement of the gamma locus; this is apparently based on IL-7 inducing a selective accessibility of the gamma locus to the VDJ recombinase. The coding joints created by VDJ recombination were known to be modified by enzymatic processes. We observed for the first time that signal joints were also modified by TdT and by exonucleolytic enzymes, suggesting that signal joint closure is achieved by the recombinase complex. We also investigated the lineage relationship of T cells and NK cells. We have identified a common precursor for both lineages in the thymus, and demonstrated that single precursor cells (CD44+CD25-) can develop into alpha-beta, gamma-delta or NK cells. Induction of apoptosis has been studied. We examined the mechanism by which p53 becomes activated by ionizing radiation. We showed that the SCID kinase, contrary to previous models, is not involved in activating, and may actually attenuate, p53 functions of gene induction and apoptosis. We observed that TNF and FasL can induce extensive oxidative DNA damage and chromosomal aberratations, suggesting possible roles in oncogenesis. FasL was successfully expressed in a poxvirus. This may be useful for expressing FasL in an allograft which could protect the graft from immune rejection.
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