Defective development of NK1.1(+) T-cell antigen receptor alpha beta(+) 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 w as analyzed in zeta-associated protein 70 (ZAP-70) null ((-/-)) mice. Both NK1.1(+) TCR alpha beta (+) and NK1.1(+) TCR gamma delta (+) cell populatio ns 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(-) thymocyt es 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 wit h NK1.1(+) T cells. The NK1.1(+) CD3(-) cells produced interferon-gamma upo n stimulation with NK1.1 cross-linking in the presence of interleukin-2 and exhibited a substantial cytotoxicity against YAC-1 cells. Moreover, the ge neration of NK1.1(+) T cells with invariant V alpha 14J alpha 281 chains wa s induced from the NK1.1(+) CD3(-) thymocytes following stimulation with ph orbol myristate acetate and ionomycin in a neonatal thymic organ culture. A n introduction of TCR alpha and beta transgenes to the ZAP-70(-/-) mice res ulted in generation of an NK1.1(+) TCR alpha beta (dim) population, whereas no substantial CD4(+) CD8(-) or CD4(-) CD8(+) population that expressed th e introduced TCR alpha beta was generated in the mainstream T lineage. Thes e findings demonstrate that ZAP-70 kinase is indispensable for the developm ent of NK1.1(+) T cells and that the unique NK1.1(+) CD3(-) thymocytes in Z AP-70(-/-) mice contain immediate precursors of NK1.1(+) T cells, (Blood. 2 001;97:1765-1775) (C) 2001 by The American Society of Hematology.