Defective development of NK1.1+ T-cell antigen receptor alphabeta+ cells in zeta-associated protein 70 null mice with an accumulation of NK1.1+ CD3- NK-like cells in the thymus.

Development of natural killer 1.1 + (NK1.1 + ) CD3 + (NK1.1 + T) cells was analyzed in zeta-associated protein 70 (ZAP-70) null ( −/− ) mice. Both NK1.1 + TCRαβ + and NK1.1 + TCRγδ + cell populations were absent in the thymus and spleen. By contrast, the number of NK1.1 + CD3 − cells was increased in these tissues. The NK1.1 + CD3 − thymocytes in ZAP-70 −/− mice had surface phenotypes in common with NK or NK1.1 + T cells. However, some of them were discordant either with NK cells or with NK1.1 + T cells. The NK1.1 + CD3 − cells produced interferon-γ upon stimulation with NK1.1 cross-linking in the presence of interleukin-2 and exhibited a substantial cytotoxicity against YAC-1 cells. Moreover, the generation of NK1.1 + T cells with invariant Vα14Jα281 chains was induced from the NK1.1 + CD3 − thymocytes following stimulation with phorbol myristate acetate and ionomycin in a neonatal thymic organ culture. An introduction of TCRα and β transgenes to the ZAP-70 −/− mice resulted in generation of an NK1.1 + TCRαβ dim population, whereas no substantial CD4 + CD8 − or CD4 − CD8 + population that expressed the introduced TCRαβ was generated in the mainstream T lineage. These findings demonstrate that ZAP-70 kinase is indispensable for the development of NK1.1 + T cells and that the unique NK1.1 + CD3 − thymocytes in ZAP-70 −/− mice contain immediate precursors of NK1.1 + T cells.