Natural Killer Dendritic Cells Have Both Antigen Presenting and Lytic Function and in Response to CpG Produce IFN-γ via Autocrine IL-12

Abstract

We have isolated rare cells bearing the NK cell surface marker NK1.1, as well as the dendritic cell (DC) marker CD11c, from the spleen, liver, lymph nodes, and thymus of normal mice. These cells possess both NK cell and DC function because they can lyse tumor cells and subsequently present Ags to naive Ag-specific T cells. Interestingly, in response to IL-4 plus either IL-2 or CpG, NKDC produce more IFN-γ than do DC, or even NK cells. We determined that CpG, but not IL-2, induces NKDC to secrete IFN-γ via the autocrine effects of IL-12. In vivo, CpG dramatically increases the number of NKDC. Furthermore, NKDC induce greater Ag-specific T cell activation than do DC after adoptive transfer. Their unique ability to lyse tumor cells, present Ags, and secrete inflammatory cytokines suggests that NKDC may play a crucial role in linking innate and adaptive immunity.

The ‘kiss of death’ by dendritic cells to cancer cells

“…They are characterized by the production of large amounts of IFN-g secretion in response to a combination of CpG þ IL-4 or IL-12 þ IL-18. 55,58 Hence, the authors demonstrated that contamination of DC preparations with NKDCs accounted for the controversial production of IFN-g by DCs. More interestingly, the authors showed that, subsequent to OVA-loaded YAC-1 cell killing, NKDCs up-took and presented OVA antigen to specific class-I restricted T cells, thus claiming the benefit of these cells to kill their target and directly cross-present resultant antigen to specific T cells.…”

“…In mice, two subsets of cells with bitypic NK and DC phenotypic and functional characteristics have been recently discovered and termed NKDCs and interferonproducing killer DCs (IKDCs). 55,56,78 It remains unclear how closely related these two subsets are or whether they are indeed identical. The phenotypic and functional characteristics of both subsets are summarized in Table 2.…”

“…The phenotypic and functional characteristics of both subsets are summarized in Table 2. Dematteo's group 55 first described NKDCs as a subset of DCs capable to kill tumors and present antigens. NKDCs are mainly phenotypically defined by their coexpression of CD11c and NK1.1.…”

“…Second, the phenotypic characterization of NKDCs showed a significant phenotypic heterogeneity with, for example, NK1.1 þ CD49b À cells. 55 As a consequence, the ability of NKDCs to cross-present antigens provided by their apoptotic target cells remained questionable by the possible contamination with APCs and/ or NK cells during isolation.…”

Interleukin-15 liver gene transfer increases the number and function of IKDCs and NK cells

“…1 IKDCs, through a direct tumoricidal activity, have been implicated in the innate immunotherapeutic effects of a combination of interleukin (IL)-2 plus imatinib against B16F10-derived melanomas. 2 Previous reports had also postulated the existence of a population of cells sharing some of the functional and phenotypical features of both NK cells and DCs in mice, 3 mainly on the basis of CD11c and NK1.1 coexpression. There is evidence that these so-called NKDCs (that comprise the IKDC subset) play an important role in the defense against Listeria primarily by producing IFN-g in response to IL-12 and IL-18.…”