Final steps of natural killer cell maturation: a model for type 1 type 2 differentiation?

Analysis of cytokine and differentiation antigen expression in human natural killer (NK) cells revealed that interleukin 13 (IL-13) and interferon gamma (IFN-gamma) are produced at sequential stages during irreversible IL-12-induced differentiation. In human NK cell clones, polyclonal CD3(-)CD161(+)CD56(-) cells and peripheral lymphocytes, IL-4 induced the proliferation of both IL-13. NK and T cells, whereas IL-12 allowed a proliferation-independent accumulation of IFN-gamma (+) cells. These data disproved the NK1-NK2 hypothesis and challenge the current T helper 1 (THI)-T(H)2 paradigm. We propose that the cytokine environment regulates a type 2 -->0 -->1 developmental progression, with IL-12 needed for terminal differentiation and IL-4 delaying this process, rather than a type 1 versus type 2 decision of a type 0 cell.