The IL-12 Signature: NK Cell Terminal CD56+high Stage and Effector Functions

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Abstract
We report that human peripheral NK cells expressing high CD56 levels (CD56+high) are terminally differentiated cells indistinguishable from mature NK cells recently activated in the presence of IL-12, and not a functionally distinct NK-cell subset or progenitors to mature CD56+low NK cells. CD56+high NK cells coexpress all differentiation Ags constitutive or inducible in mature (CD56+) NK cells, except CD16, present at lower level than on most mature NK cells. Also, activation markers, activating receptors and adhesion molecules, and most inducible receptors are expressed exclusively and constitutively and are inducible at higher levels on CD56+high than on CD56+low NK cells. Consistent with their activated phenotype, many CD56+high NK cells are cycling and mediate heightened effector functions (proliferation, IFN-γ and IL-10 but not IL-13 production) in response to IL-12 and other NK cell-specific stimuli. Conversely, IL-12 induces on CD56+low NK cells all markers constitutively expressed on the CD56+high NK cells, concomitantly preventing the IL-2 (and IL-15)-inducible expression of NKp44 and CD16 re-expression after immune complex-induced down-modulation, and CD56−/+low NK cells acquire a CD56+high NK cell phenotype in short term in vitro culture with IL-12. The significance of these findings to the NK cell-mediated regulation of immune responses and NK cell development is discussed.

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