Expression of type 1 (interferon gamma) and type 2 (interleukin-13, interleukin-5) cytokines at distinct stages of natural killer cell differentiation from progenitor cells

Abstract

To determine whether production of type 1 and type 2 cytokines defines discrete stages of natural killer (NK) cell differentiation, cytokine expression was analyzed in human NK cells generated in vitro in the presence of interleukin-15 (IL-15) and/or IL-2 from umbilical cord blood hematopoietic progenitors. Like peripheral NK cells, the CD161+/CD56+ NK cells from these cultures contained a tumor necrosis factor alpha (TNF-α)+/granulocyte macrophage–colony-stimulating factor (GM-CSF)+ subset, an interferon gamma (IFN-γ)+ subset, mostly included within the former, and very few IFN-γ−/IL-13+ cells. Instead, most immature CD161+/CD56− NK cells, detectable only in the cultures with IL-2, produced IL-13, TNF-α, and GM-CSF, but not IFN-γ, and contained an IL-5+ subset. In short-term cultures with IL-12 and feeder cells, a proportion of the immature cells acquired the ability to produce IFN-γ. Part of these produced both IFN-γ and IL-13, irrespective of induced CD56 expression. These in vitro data indicate that ability to produce the type 2 cytokines IL-13 and IL-5 defines CD161+ NK cells at intermediate stages of differentiation, and is lost upon terminal functional differentiation, concomitant with acquired ability to produce IFN-γ.