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

Abstract

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+ TCRαβdim 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.