Phenotypic and Functional Activation of Hyporesponsive KIR(neg)NKG2A(neg) Human NK-Cell Precursors Requires IL12p70 Provided by Poly(I:C)-Matured Monocyte-Derived Dendritic Cells

作者：Curran Shane A^*; Romano Emanuela; Kennedy Michael G; Hsu Katharine C; Young James W

来源：Cancer Immunology Research, 2014, 2(10): 1000-1010.

DOI：10.1158/2326-6066.CIR-14-0054-T

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 KIRs 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 (DC) reconstitute with comparable kinetics with donor NK cells after alloHSCT, we used hyporesponsive KIR(neg)NKG2A(neg) precursor cells to evaluate how specific DC subtypes generate a functionally active NK-cell repertoire. Both monocyte-derived DCs (moDC) and Langerhans-type DCs (LC) induce KIR(neg)NKG2A(neg) precursor cells to express the inhibitory receptors NKG2A and KIR, without requiring cell proliferation. Poly(I:C)-matured moDCs significantly augmented the expression of NKG2A, but not KIR, in an IL12p70-dependent manner. Although all DC-stimulated KIR(neg)NKG2A(neg) 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 IL12p70-producing, poly(I:C)-matured moDCs. This critical ability of poly(I:C)-matured moDCs to provide IL12p70 to developing KIR(neg)NKG2A(neg) precursors results in a dominant, multifunctional, NKG2A(pos) NK-cell population that is capable of both cytolysis and IFNg production. Poly(I:C)-matured moDCs are, therefore, the most effective conventional DC subtype for generating a functionally competent NK-cell repertoire by an IL12p70-dependent mechanism.

• 出版日期2014-10