A functionally responsive natural killer (NK) cell repertoire requires the acquisition of inhibitory NKG2A and killer immunoglobulin-like receptors (KIR) through pathways that remain undefined. Functional donor NK cells expressing KIR for non-self class I MHC ligands contribute to a positive outcome after allogeneic hematopoietic stem cell transplantation (alloHSCT) by targeting HLA-matched recipient leukemic cells. Insofar as circulating donor conventional dendritic cells (DCs) reconstitute with comparable kinetics to donor NK cells after alloHSCT, we used hyporesponsive KIRnegNKG2Aneg precursor cells to evaluate how specific DC subtypes generate a functionally active NK cell repertoire. Both monocyte-derived DCs (moDCs) and Langerhans-type DCs (LCs) induce KIRnegNKG2Aneg precursor cells to express the inhibitory receptors NKG2A and KIR, without requiring their proliferation. Poly(I:C) matured moDCs significantly augmented NKG2A but not KIR expression in an IL-12p70 dependent manner. While all DC stimulated KIRnegNKG2Aneg cells were able to acquire cytolytic activity against class I MHC-negative targets, the ability to secrete IFN-gamma was restricted to cells that were stimulated by IL-12p70 producing poly(I:C) matured moDCs. This critical ability of poly(I:C) matured moDCs to provide IL-12p70 to developing KIRnegNKG2Aneg precursors results in a dominant multi-functional NKG2Apos population that is capable of both cytolysis and IFN-gamma production. Poly(I:C) matured moDCs are therefore the most effective conventional DC subtype for generating a functionally competent NK cell repertoire by an IL-12p70 dependent mechanism.
- Received March 28, 2014.
- Revision received June 19, 2014.
- Accepted June 30, 2014.
- Copyright © 2014, American Association for Cancer Research.