Editors' ChoiceImmunology

NK Cells Attack Pancreatic Beta Cells

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Science Signaling  26 Jan 2010:
Vol. 3, Issue 106, pp. ec30
DOI: 10.1126/scisignal.3106ec30

Although natural killer (NK) cells have been implicated in the pathogenesis of type 1 diabetes, the mechanism whereby they contribute to this autoimmune disorder—which depends on destruction of pancreatic beta cells by autoreactive T cells—has been unclear. Gur et al. wondered whether natural cytotoxicity receptor NKp46, an activating NK cell receptor that has been implicated in tumor immunity and control of influenza despite having no known ligand (see Colucci and Cilio), might play a role. They found that fusion proteins of NKp46 or the mouse ortholog NCR1 with immunoglobulin (NKp46-Ig and NCR1-Ig, respectively) recognized human and mouse beta cells but no other pancreatic cells. Immunohistochemical analysis of nonobese diabetic mice (NOD mice, a model of type 1 diabetes) revealed that the NKp46 ligand was present before the development of the pancreatic islet inflammation that precedes diabetes (insulinitis) and throughout the development of diabetes. A comparison of mouse NK cells with NCR1 to NK cells lacking NCR1 indicated that, although beta cells failed to elicit cytokine secretion, they stimulated NK cell degranulation; indeed, NK cells isolated from islets of prediabetic NOD mice showed substantial degranulation. Mice lacking NCR1 were resistant to the development of type 1 diabetes in response to injection with low-dose streptozotocin (LDST), and NK cells appeared in the pancreas of NOD and LDST mice during insulinitis, becoming most abundant at the prediabetic stage, during the transition from insulinitis to diabetes. Injection of NKp46-Ig or NCR1-Ig into NOD mice, which stimulated the production of antibodies directed against NKp46 or NCR1, respectively, decreased the surface abundance of NCR1, inhibited beta cell–induced NK cell degranulation, and prevented the development of diabetes, even when administered at the late prediabetic stage. The authors thus conclude that a ligand to NKp46 is present on pancreatic beta cells and that this NK cell receptor is crucial to the development of type 1 diabetes.

C. Gur, A. Porgador, M. Elboim, R. Gazit, S. Mizrahi, N. Stern-Ginossar, H. Achdout, H. Ghadially, Y. Dor, T. Nir, V. Doviner, O. Hershkovitz, M. Mendelson, Y. Naparstek, O. Mandelboim, The activating receptor NKp46 is essential for the development of type 1 diabetes. Nat. Immunol. 11, 121–128 (2010). [PubMed]

F. Colucci, C. M. Cilio, Taming killer cells may halt diabetes progression. Nat. Immunol. 11, 111–112 (2010). [PubMed]

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