Distinction between IL-13+ and IFN-γ+ natural killer cells and regulation of their pool size by IL-4

Abstract

The hypothesis that distinct subsets of NK cells produce type 2 and type 1 cytokines in resting naive lymphocytes was tested analyzing cytokine production at the single-cell level. Two non-overlapping IL-13⁺ and IFN-γ⁺ subsets were identified in adult and neonatal NK cells. IL-2 maintained their relative proportion. Accumulation of the former was induced by IL-4, but not IL-13, and inhibited by IL-12; that of the latter was induced by IL-12 and inhibited by IL-4 and IL-13. IL-4 induced preferential proliferation of the pre-existing peripheral IL-13⁺ cells, whereas IL-12 had minimal effect on proliferation of the IFN-γ⁺ NK cells. The IL-13⁺ cells (CD161⁺ only) are phenotypically distinct from the IFN-γ⁺ones (CD56⁺) before and after culture under any condition analyzed, and produce IL-13 in response to NK-sensitive target cells and PMA + Ca²⁺ ionophore, whereas also FcγRIIIA and IL-2 + IL-12 stimulate IFN-γ production. These data define the existence and regulation of two distinct resting peripheral NK cell subsets producing type 1 and type 2 cytokines, and suggest possible roles for IL-13⁺ NK cells in allergy.