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Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Addenbrooke’s Hospital, Cambridge, United Kingdom
NK cells from NOD mice induced with poly(I:C) in vivo exhibit low cytotoxicity against a range of target cells, but the genetic mechanisms controlling this defect are yet to be elucidated. Defects in the expression of NKG2D and its ligands, the RAE-1 molecules, have been hypothesized to contribute to the reduced NK function present in NOD mice. In this study, we show that segregation of the NK-mediated killing phenotype did not correlate with the NOD Raet1 haplotype and that the large alterations in NKG2D expression previously reported on NK cells expanded in vitro were not observed in primary, poly(I:C)-elicited NK cells in vivo. Additional studies indicate a complex genetic control of defective NOD NK cells including genes linked to the MHC and possibly those that are associated with an altered cytokine response to the TLR3-agonist poly(I:C).
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1 L.S.W. and J.A.T. are supported by a grant from the Juvenile Diabetes Research Foundation and the Wellcome Trust, and LSW is Juvenile Diabetes Research Foundation/Wellcome Trust Principal Research Fellow. The Cambridge Institute for Medical Research is in receipt of a Wellcome Trust Strategic Award (079895). The availability of NOD congenic mice through the Taconic Farms Emerging Models Program has been supported by grants from the Merck Genome Research Institute, National Institute of Allergy and Infectious Diseases, and the Juvenile Diabetes Research Foundation. L.M.M. is a Juvenile Diabetes Research Foundation Postdoctoral Fellow.
2 Current address: Division of Molecular Immunology, Center for Neurologic Diseases, Brigham and Women’s Hospital and Harvard Medical School, New Research Building, 77 Louis Pasteur Avenue, Boston, MA 02115.
3 Address correspondence and reprint requests to Prof. Linda Wicker, Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, Cambridge Institute for Medical Research, Wellcome Trust/Medical Research Council Building, Addenbrooke’s Hospital, Cambridge, CB2 0XY, U.K. E-mail address: linda.wicker{at}cimr.cam.ac.uk
4 Abbreviations used in this paper: T1D, type 1 diabetes; QPCR, quantitative real-time PCR; MFI, mean fluorescence intensity; DC, dendritic cell; Ct, cycle threshold.
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