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The activating receptor NKp46 is essential for the development of type 1 diabetes

Nature Immunology volume 11, pages 121–128 (2010)Cite this article

Abstract

The mechanism of action of natural killer (NK) cells in type 1 diabetes is still unknown. Here we show that the activating receptor NKp46 recognizes mouse and human ligands on pancreatic beta cells. NK cells appeared in the pancreas when insulitis progressed to type 1 diabetes, and NKp46 engagement by beta cells led to degranulation of NK cells. NKp46-deficient mice had less development of type 1 diabetes induced by injection of a low dose of streptozotocin. Injection of soluble NKp46 proteins into nonobese diabetic mice during the early phase of insulitis and the prediabetic stage prevented the development of type 1 diabetes. Our findings demonstrate that NKp46 is essential for the development of type 1 diabetes and highlight potential new therapeutic modalities for this disease.

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Figure 1: NKp46 recognizes a ligand (or ligands) on beta cells.
Figure 2: NKp46-Ig recognizes mouse and human beta cells in situ.
Figure 3: NKp46-mediated killing of beta cells.
Figure 4: Impaired diabetes development in the absence of NKp46.
Figure 5: Appearance of NK cells in the pancreas during the development of diabetes.
Figure 6: Treatment with NKp46-Ig fusion proteins prevents the development of diabetes in NOD mice.
Figure 7: Impaired NKp46 function.
Figure 8: Treatment with NKp46 at a late prediabetic stage prevents the development of diabetes.

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Acknowledgements

We thank E. Pikarsky for help and advice; E. Horowitz for assistance; members of the Mandelboim laboratory for discussions and the Physician Research Program of Hadassah Hospital for assistance. Supported by the Juvenile Diabetes Research Foundation (O.M.), the Israel Science Foundation (Morasha grant to C.G.) and the Leifermann Foundation (Y.N.).

Author information

Author notes

  1. Angel Porgador, Yaakov Naparstek and Ofer Mandelboim: These authors equally contributed to this work.

Authors and Affiliations

  1. The Lautenberg Center for General and Tumor Immunology, Hebrew University Hadassah Medical School, Institute for Medical Research Israel–Canada, Jerusalem, Israel

    Chamutal Gur, Moran Elboim, Roi Gazit, Saar Mizrahi, Noam Stern-Ginossar, Hagit Achdout, Hormas Ghadially & Ofer Mandelboim

  2. Department of Medicine, Hadassah–Hebrew University Hospital, Jerusalem, Israel

    Chamutal Gur & Yaakov Naparstek

  3. The Shraga Segal Department of Microbiology and Immunology and the National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Israel

    Angel Porgador, Oren Hershkovitz & Michal Mendelson

  4. Developmental Biology and Cancer Research, Hebrew University Hadassah Medical School, Institute for Medical Research Israel–Canada, Jerusalem, Israel

    Yuval Dor & Tomer Nir

  5. Department of Pathology, Hadassah–Hebrew University Hospital, Jerusalem, Israel

    Victoria Doviner

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  1. Chamutal Gur
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Contributions

C.G. designed all experiments, did all experiments, analyzed the data and wrote the manuscript; A.P. made the initial observation that NKp46 recognizes beta cells and supervised the project; M.E., R.G., S.M., N.S.-G., H.A., H.G., T.N., O.H. and M.M. contributed reagents; Y.D. provided guidance and reagents; V.D. helped in the immunohistochemical experiments and in determining the insulitis scoring; Y.N. supervised the project and contributed reagents; and O.M. supervised the entire project and analyzed the data, and all experiments were done in the O.M. laboratory under the guidance of O.M.

Corresponding authors

Correspondence to Angel Porgador or Ofer Mandelboim.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–4 (PDF 194 kb)

Supplementary Movie 1

Early PBS treated group. (WMV 3016 kb)

Supplementary Movie 2

Early NKp46 treated group. (WMV 1316 kb)

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Gur, C., Porgador, A., Elboim, M. et al. The activating receptor NKp46 is essential for the development of type 1 diabetes. Nat Immunol 11, 121–128 (2010). https://doi.org/10.1038/ni.1834

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