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Interferon-producing killer dendritic cells provide a link between innate and adaptive immunity

Nature Medicine volume 12, pages 207–213 (2006)Cite this article

Abstract

Natural killer (NK) cells and dendritic cells (DCs) are, respectively, central components of innate and adaptive immune responses1,2. We describe here a third DC lineage, termed interferon-producing killer DCs (IKDCs), distinct from conventional DCs and plasmacytoid DCs and with the molecular expression profile of both NK cells and DCs. They produce substantial amounts of type I interferons (IFN) and interleukin (IL)-12 or IFN-γ, depending on activation stimuli. Upon stimulation with CpG oligodeoxynucleotides, ligands for Toll-like receptor (TLR)-9, IKDCs kill typical NK target cells using NK-activating receptors. Their cytolytic capacity subsequently diminishes, associated with the loss of NKG2D receptor (also known as Klrk1) and its adaptors, Dap10 and Dap12. As cytotoxicity is lost, DC-like antigen-presenting activity is gained, associated with upregulation of surface major histocompatibility complex class II (MHC II) and costimulatory molecules, which formally distinguish them from classical NK cells. In vivo, splenic IKDCs preferentially show NK function and, upon systemic infection, migrate to lymph nodes, where they primarily show antigen-presenting cell activity. By virtue of their capacity to kill target cells, followed by antigen presentation, IKDCs provide a link between innate and adaptive immunity.

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Figure 1: Comparative phenotypic and morphologic characterization of IKDCs, PDCs and NK cells.
Figure 2: Cytotoxic activity and cytokines production by activated splenic IKDCs.
Figure 3: The transition of splenic IKDCs from cytotoxic to APCs upon activation with CpG ODN.
Figure 4: In vitro and in vivo antigen presentation by IKDCs.

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Acknowledgements

We thank L. Zitvogel's group for communicating its data on IKDCs; K. Palucka and J. Banchereau for discussions. We also thank M. Delannoy for his technical assistance with electronic microscopy. We thank C. Chia and L.S. Laird for their help on the adoptive transfer experiments, and M. Jones for her technical assistance in immunofluorescence techniques. We thank F. Murillo for his technical assistance with microarray techniques. C.W.C. is supported by a Cancer Research Institute postdoctoral fellowship. This work was supported by grants from the US National Institutes of Health (NIH), the Janney Fund and Seraph Foundation, and gifts from Bill and Betty Topecer and Dorothy Needle. L.L.L. is an American Cancer Society Research Professor and is funded by NIH grants CA89189 and CA89294.

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Authors and Affiliations

  1. Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, CRB-440, 1650 Orleans Street, Baltimore, 21231, Maryland, USA

    Camie W Chan, Emily Crafton, Hong-Ni Fan, James Flook, Kiyoshi Yoshimura, Mario Skarica, Drew M Pardoll & Franck Housseau

  2. Cerus Corporation, 2411 Stanwell Drive, Concord, 94520, California, USA

    Dirk Brockstedt & Thomas W Dubensky

  3. Department of Pediatrics, Division of Infectious Diseases, Johns Hopkins University Medical School, 720 Rutland Avenue, Ross 1170, Baltimore, 21205, Maryland, USA

    Monique F Stins

  4. Department of Microbiology and Immunology and the Cancer Research Institute, University of California San Francisco, 513 Parnassus Avenue, HSE 420, San Francisco, 94143, California, USA

    Lewis L Lanier

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Supplementary information

Supplementary Fig. 1

Mouse strain differences of IKDCs and PDCs. (PDF 22 kb)

Supplementary Fig. 2

Morphology of fresh and CpG ODN 1668–activated IKDCs. (PDF 50 kb)

Supplementary Fig. 3

IKDCs are detected in a variety of tissues. (PDF 102 kb)

Supplementary Fig. 4

In vivo localization of CFSE-labeled IKDCs in spleen and lymph nodes. (PDF 69 kb)

Supplementary Table 1

Expression levels of selected genes that are highly expressed in spleen IKDCs versus PDCs and cDCs, using microarray analysis. (PDF 37 kb)

Supplementary Methods (PDF 54 kb)

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Chan, C., Crafton, E., Fan, HN. et al. Interferon-producing killer dendritic cells provide a link between innate and adaptive immunity. Nat Med 12, 207–213 (2006). https://doi.org/10.1038/nm1352

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