title: Natural killer cell function, an important target for infection and tumor protection, is impaired in type 2 diabetes.
abstract: Patients with Type 2 diabetes (T2D) are highly susceptible to infection and have an increased incidence of some tumors, possibly due to immune system dysfunction. In the innate cellular immune system, Natural Killer (NK) lymphocytes are important effectors responsible for controlling infections and combating tumor development. We analyzed NK cell subsets in 51 patients with long-standing T2D. Compared with healthy blood donors, diabetic patients showed a profound decrease in both NKG2D-positive NK cells (44% vs. 55.5%, P<0.01) and NKp46-positive cells (26% vs. 50%, P<0.01). Decreased expression of these receptors was associated with functional defects, such as reduced NK degranulation capacity when challenged with the tumor target cell line K562 (10.3 vs. 15.8%, P<0.05). This defect could be restored in vitro by stimulating NK cells from T2D patients with IL-15 (P<0.05). NKG2D expression was found to be negatively correlated with HBA1c level (r=-0.50; P=0.009), suggesting that sustained hyperglycemia could directly influence NK cell defects. We demonstrated that endoplasmic reticulum (ER) stress, an important mediator in diabetes-associated complications, was inducible in vitro in normal NK cells and that tunicamycin treatment resulted in a significant decrease in NKG2D expression (P<0.05). Furthermore, markers of the Unfolded Protein Response (UPR) BiP, PDI and sXBP1 mRNAs were significantly increased in NK cells from T2D patients (P<0.05, P<0.01, P<0.05, respectively), indicating that ER stress is activated in vivo through both PERK and IRE1 sensors. These results demonstrate for the first time defects in NK cell-activating receptors NKG2D and NKp46 in T2D patients, and implicate the UPR pathway as a potential mechanism. These defects may contribute to susceptibility to infections and malignancies and could be targetted therapeutically.
authors: Institut National de la Santé et de la Recherche Médicale (INSERM), UMR 940, Paris, France.
authors: Jeannig
authors: J
authors: Berrou
authors: Sophie
authors: S
authors: Fougeray
authors: Marion
authors: M
authors: Venot
authors: Victor
authors: V
authors: Chardiny
authors: Jean-François
authors: JF
authors: Gautier
authors: Nicolas
authors: N
authors: Dulphy
authors: Antoine
authors: A
authors: Toubert
authors: Marie-Noëlle
authors: MN
authors: Peraldi
mesh_terms: D000328:Adult; D000368:Aged; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress / Q000276:immunology; D005260:Female; D006801:Humans; D006943:Hyperglycemia / Q000276:immunology; D007239:Infections / Q000276:immunology*; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000235:genetics / Q000378:metabolism; D055627:Natural Cytotoxicity Triggering Receptor 1 / Q000235:genetics / Q000378:metabolism; D009369:Neoplasms / Q000276:immunology*; D010641:Phenotype; D014158:Transcription, Genetic / Q000276:immunology; D055815:Young Adult
chemical_list: C527085:KLRK1 protein, human; C112260:NCR1 protein, human; D055655:NK Cell Lectin-Like Receptor Subfamily K; D055627:Natural Cytotoxicity Triggering Receptor 1
references: Diabetes Res Clin Pract. 2007 Apr;76(1):44-50
references: 16959366
references: J Exp Med. 2010 Feb 15;207(2):269-72
references: 20142428
references: Annu Rev Pathol. 2008;3:399-425
references: 18039139
references: Nat Rev Immunol. 2007 Sep;7(9):737-44
references: 17673918
references: Exp Hematol. 2006 Jun;34(6):753-9
references: 16728280
references: Obesity (Silver Spring). 2009 Mar;17(3):601-5
references: 19238145
references: Diabetologia. 2012 May;55(5):1366-79
references: 22396011
references: Nat Rev Immunol. 2003 Oct;3(10):781-90
references: 14523385
references: Nephrol Dial Transplant. 2010 Feb;25(2):449-57
references: 19793928
references: Nat Rev Immunol. 2003 May;3(5):413-25
references: 12766763
references: Nat Immunol. 2010 Feb;11(2):121-8
references: 20023661
references: Annu Rev Immunol. 2001;19:197-223
references: 11244035
references: J Immunol Methods. 2009 Feb 28;341(1-2):154-64
references: 19056395
references: Proc Natl Acad Sci U S A. 2002 Mar 5;99(5):2977-82
references: 11830641
references: Proc Natl Acad Sci U S A. 1996 Aug 6;93(16):8584-9
references: 8710914
references: Nat Immunol. 2002 Jan;3(1):6-8
references: 11753399
references: Clin Exp Immunol. 2010 Jul 1;161(1):48-56
references: 20408863
references: Nature. 2008 Jul 24;454(7203):455-62
references: 18650916
references: Cell Death Differ. 2006 Mar;13(3):393-403
references: 16397582
references: Annu Rev Biochem. 2005;74:739-89
references: 15952902
references: Diabetes. 2007 Jan;56(1):177-85
references: 17192480
references: Nat Immunol. 2006 May;7(5):517-23
references: 16565719
references: J Clin Invest. 2009 May;119(5):1251-63
references: 19349689
references: Blood. 2008 Jul 1;112(1):82-9
references: 18316629
references: Circulation. 2011 Dec 20;124(25):2933-43
references: 22104546
references: Science. 1999 Jul 30;285(5428):727-9
references: 10426993
references: Diabet Med. 2008 Feb;25(2):157-64
references: 18290856
references: Immunol Rev. 2001 Jun;181:203-14
references: 11513142
references: Diabetes Care. 2010 Jul;33(7):1674-85
references: 20587728
references: Trends Immunol. 2001 Nov;22(11):633-40
references: 11698225
references: J Biochem. 2010 Apr;147(4):471-83
references: 19919955
references: Nat Immunol. 2005 Sep;6(9):928-37
references: 16116470
references: J Immunol. 2009 Feb 1;182(3):1696-705
references: 19155520
references: Nat Rev Immunol. 2007 Sep;7(9):703-14
references: 17717540
references: Blood. 2005 Nov 15;106(10):3366-9
references: 16002429
references: Hum Immunol. 1999 Apr;60(4):323-30
references: 10363723
references: Diabet Med. 2010 Jun;27(6):673-8
references: 20546286
references: J Exp Med. 2009 Jan 16;206(1):25-34
references: 19103877
references: Exp Diabetes Res. 2012;2012:481840
references: 22474423
references: N Engl J Med. 1999 Dec 16;341(25):1906-12
references: 10601511
references: Diabetes. 2012 Feb;61(2):492-504
references: 22228718
references: Science. 2004 Nov 26;306(5701):1517-9
references: 15567854