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Altered Natural Killer Cells in Type 1 Diabetic Patients

¹ Joslin Diabetes Center, Boston, Massachusetts
² Division of Endocrinology, Children’s Hospital Boston, Boston, Massachusetts
³ Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts

Address correspondence and reprint requests to Christophe Benoist or Diane Mathis, Harvard Medical School, One Joslin Place, Boston, MA 02215. E-mail : cbdm{at}joslin.harvard.edu

Abbreviations: DKA, diabetic ketoacidosis; DPT-1, Diabetes Prevention Trial of Type 1 Diabetes; IFN-, -interferon; MFI, mean fluorescence intensity; NCR, natural killer–activating receptor; NK, natural killer; SNP, single-nucleotide polymorphism; TNF-, tumor necrosis factor-

Evidence from animal models suggests that natural killer (NK) cells can be important players in the development of type 1 diabetes, although data in humans are still sparse. We studied the frequency and activation state of blood NK cells at different stages of human type 1 diabetes, and whether genetic or phenotypic NK cell peculiarities could be associated with an early onset of diabetes. The onset period is marked by a slight reduction in blood NK cells, but these are unusually activated in some patients (-interferon expression). This activation status does not correlate, however, with a particularly young age at onset. In contrast, NK cells in patients with long-standing type 1 diabetes had a markedly lower expression of p30/p46 NK-activating receptor molecules compared with those of control subjects. A slightly decreased expression of NKG2D in all type 1 diabetic patients relative to control subjects was observed, independent of the duration of disease, parallel to prior observations in the NOD mouse. Finally, type 1 diabetic patients had an increased frequency of KIR gene haplotypes that include the activating KIR2DS3 gene, with a genetic interaction between the KIR and HLA complexes. The reduced activation of NK cells in individuals with long-standing type 1 diabetes would seem to be a consequence rather than a cause, but other peculiarities may relate to type 1 diabetes pathogenesis.

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