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

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-gamma+ 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-gamma+ NK cells. The IL-13+ cells (CD161+ only) are phenotypically distinct from the IFN-gamma+ ones (CD56+) before and after culture under any condition analyzed, and produce IL-13 in response to NK-sensitive target cells and PMA+Ca(2+) ionophore, whereas also FcgammaRIIIA and IL-2+IL-12 stimulate IFN-gamma 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.