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Mutual activation of natural killer cells and monocytes mediated by NKp80-AICL interaction

Nature Immunology volume 7, pages 1334–1342 (2006)Cite this article

Abstract

Receptors encoded by the natural killer (NK) cell gene complex (such as NKG2D) govern the reactivity of NK cells. However, the function and ligand(s) of the NK cell gene complex–encoded human NK cell receptor NKp80 remain elusive. Here we demonstrate that NKp80 binds to the genetically linked 'orphan' receptor AICL, which, like NKp80, is absent from rodents. We defined AICL as a myeloid-specific activating receptor that is upregulated by Toll-like receptor stimulation. AICL-NKp80 interactions promoted NK cell–mediated cytolysis of malignant myeloid cells. In addition, during crosstalk between NK cells and monocytes, NKp80 stimulated the release of proinflammatory cytokines from both cell types. Thus, by specifically bridging NK cells and myeloid cells, NKp80-AICL interactions may contribute to the initiation and maintenance of immune responses at sites of inflammation.

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Figure 1: NKp80 stimulates granule exocytosis and cytokine secretion.
Figure 2: NKp80 engages AICL.
Figure 3: AICL is a myeloid-specific receptor.
Figure 4: AICL is upregulated by TLR stimulation and stimulates TNF release.
Figure 5: The NKp80-AICL interaction promotes NK cell–mediated cytolysis of myeloid cells.
Figure 6: NKp80-dependent stimulation of cytokine release.

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Acknowledgements

We thank W. Ruschmeier for technical assistance, J. Bukur for CD161-ED, J. Pfeiffer for real-time PCR, A. Kelp for enhanced green fluorescent protein constructs, S. Stevanovic for mass spectrometry, and H.-G. Rammensee for long-term support and critical remarks; R848 was from S. Bauer (Philipps University Marburg). Supported by Deutsche Forschungsgemeinschaft (STE 828/3-1 and SFB 685 TP A1).

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Authors and Affiliations

  1. Department of Immunology, Institute for Cell Biology, Eberhard Karls University of Tübingen, Tübingen, 72076, Germany

    Stefan Welte, Sabrina Kuttruff, Inja Waldhauer & Alexander Steinle

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  1. Stefan Welte
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  2. Sabrina Kuttruff
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Contributions

S.W. generated monoclonal antibodies, produced recombinant NKp80, AICL and LLT1, designed and did most of the experiments and participated in writing the manuscript; S.K. analyzed the degranulation and cytokine secretion of NK cells stimulated by plate-bound antibodies; I.W. did immunoblots; and A.S. did surface plasmon resonance measurements, conceptualized the work and wrote the manuscript.

Corresponding author

Correspondence to Alexander Steinle.

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Competing interests

S.W. and A.S. have applied for a patent (submitted 6 September 2006 by the University of Tübingen) based on the results in this manuscript.

Supplementary information

Supplementary Fig. 1

Recombinant soluble ectodomains (ED) of various C-type lectin-like receptors. (PDF 129 kb)

Supplementary Fig. 2

Specificity of NKp80-specific antibodies 5D12, 10E4, and 12D11. (PDF 71 kb)

Supplementary Fig. 3

Abundance of AICL and NKp80 transcripts in leukocyte subpopulations. (PDF 30 kb)

Supplementary Fig. 4

AICL-specific antibodies. (PDF 96 kb)

Supplementary Fig. 5

Frequencies of IFN-γ-producing NK cells after 12 h co-culture with autologous CD14dimCD16+ monocytes in the presence of LPS. (PDF 84 kb)

Supplementary Table 1

AICL surface expression on human primary cells and tumor cell lines. (PDF 31 kb)

Supplementary Methods (PDF 75 kb)

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Welte, S., Kuttruff, S., Waldhauer, I. et al. Mutual activation of natural killer cells and monocytes mediated by NKp80-AICL interaction. Nat Immunol 7, 1334–1342 (2006). https://doi.org/10.1038/ni1402

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