Skip to main content

Advertisement

SpringerLink
Log in

The Expanding Role of Natural Killer Cells in Type 1 Diabetes and Immunotherapy

  • Pathogenesis of Type 1 Diabetes (A Pugliese, Section Editor)
  • Published:
Current Diabetes Reports Aims and scope Submit manuscript

Abstract

Treatments for autoimmune diseases including type 1 diabetes (T1D) are aimed at resetting the immune system, especially its adaptive arm. The innate immune system is often ignored in the design of novel immune-based therapies. There is increasing evidence for multiple natural killer (NK) subpopulations, but their role is poorly understood in autoimmunity and likely is contributing to the controversial role reported for NKs. In this review, we will summarize NK subsets and their roles in tolerance, autoimmune diabetes, and immunotherapy.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

Abbreviations

NK:

Natural killer cell

Teff :

T effector cell

Tregs :

T regulatory cells

T1D:

Type 1 diabetes

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Cooper MA, Fehniger TA, Caligiuri MA. The biology of human natural killer-cell subsets. Trends Immunol. 2001;22:633–40.

    Article  CAS  PubMed  Google Scholar 

  2. Lanier LL, Le AM, Civin CI, Loken MR, Phillips JH. The relationship of CD16 (Leu-11) and Leu-19 (NKH-1) antigen expression on human peripheral blood NK cells and cytotoxic T lymphocytes. J Immunol. 1986;136:4480–6.

    CAS  PubMed  Google Scholar 

  3. Cooper MA, Fehniger TA, Turner SC, Chen KS, Ghaheri BA, Ghayur T, et al. Human natural killer cells: a unique innate immunoregulatory role for the CD56(bright) subset. Blood. 2001;97:3146–51.

    Article  CAS  PubMed  Google Scholar 

  4. Nagler A, Lanier LL, Cwirla S, Phillips JH. Comparative studies of human FcRIII-positive and negative natural killer cells. J Immunol. 1989;143:3183–91.

    CAS  PubMed  Google Scholar 

  5. Huntington ND, Vosshenrich CA, Di Santo JP. Developmental pathways that generate natural-killer-cell diversity in mice and humans. Nat Rev Immunol. 2007;7:703–14.

    Article  CAS  PubMed  Google Scholar 

  6. Walzer T, Blery M, Chaix J, Fuseri N, Chasson L, Robbins SH, et al. Identification, activation, and selective in vivo ablation of mouse NK cells via NKp46. Proc Natl Acad Sci U S A. 2007;104:3384–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Westgaard IH, Berg SF, Vaage JT, Wang LL, Yokoyama WM, Dissen E, et al. Rat NKp46 activates natural killer cell cytotoxicity and is associated with FcepsilonRIgamma and CD3zeta. J Leukoc Biol. 2004;76:1200–6.

    Article  CAS  PubMed  Google Scholar 

  8. Peng H, Jiang X, Chen Y, Sojka DK, Wei H, Gao X, et al. Liver-resident NK cells confer adaptive immunity in skin-contact inflammation. J Clin Invest. 2013;123:1444–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Sojka DK, Plougastel-Douglas B, Yang L, Pak-Wittel MA, Artyomov MN, Ivanova Y, et al. Tissue-resident natural killer (NK) cells are cell lineages distinct from thymic and conventional splenic NK cells. Elife. 2014;3:e01659. This study identifies distinct tissue-resident NK cells in the liver and skin with differential transcriptional factor requirements than conventional, thymic and uterine NK cells.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Victorino F, Sojka DK, Brodsky KS, McNamee EN, Masterson JC, Homann D, et al. Tissue-resident NK cells mediate ischemic kidney injury and are not depleted by anti-Asialo-GM1 antibody. J Immunol. 2015;195:4973–85. This study provided the first evidence that NK subsets are differentially depleted with common depleting NK antibodies, such as anti-NK1.1 and anti-Asialo-GM1 antibodies. These results highlight the need to re-evaluate NK subsets and their impact on disease outcomes.

    Article  CAS  PubMed  Google Scholar 

  11. Dotta F, Censini S, van Halteren AG, Marselli L, Masini M, Dionisi S, et al. Coxsackie B4 virus infection of beta cells and natural killer cell insulitis in recent-onset type 1 diabetic patients. Proc Natl Acad Sci U S A. 2007;104:5115–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Brauner H, Elemans M, Lemos S, Broberger C, Holmberg D, Flodstrom-Tullberg M, et al. Distinct phenotype and function of NK cells in the pancreas of nonobese diabetic mice. J Immunol. 2010;184:2272–80.

    Article  CAS  PubMed  Google Scholar 

  13. Flodstrom M, Maday A, Balakrishna D, Cleary MM, Yoshimura A, Sarvetnick N. Target cell defense prevents the development of diabetes after viral infection. Nat Immunol. 2002;3:373–82.

    Article  CAS  PubMed  Google Scholar 

  14. Gur C, Porgador A, Elboim M, Gazit R, Mizrahi S, Stern-Ginossar N, et al. The activating receptor NKp46 is essential for the development of type 1 diabetes. Nat Immunol. 2010;11:121–8.

    Article  CAS  PubMed  Google Scholar 

  15. Poirot L, Benoist C, Mathis D. Natural killer cells distinguish innocuous and destructive forms of pancreatic islet autoimmunity. Proc Natl Acad Sci U S A. 2004;101:8102–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Bar-Ephraim YE, Mebius RE. Innate lymphoid cells in secondary lymphoid organs. Immunol Rev. 2016;271:185–99.

    Article  CAS  PubMed  Google Scholar 

  17. Fuchs A. ILC1s in tissue inflammation and infection. Front Immunol. 2016;7:104.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  18. Juelke K, Romagnani C. Differentiation of human innate lymphoid cells (ILCs). Curr Opin Immunol. 2016;38:75–85.

    Article  CAS  PubMed  Google Scholar 

  19. Chiossone L, Chaix J, Fuseri N, Roth C, Vivier E, Walzer T. Maturation of mouse NK cells is a 4-stage developmental program. Blood. 2009;113:5488–96.

    Article  CAS  PubMed  Google Scholar 

  20. Fu B, Wang F, Sun R, Ling B, Tian Z, Wei H. CD11b and CD27 reflect distinct population and functional specialization in human natural killer cells. Immunology. 2011;133:350–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Hayakawa Y, Huntington ND, Nutt SL, Smyth MJ. Functional subsets of mouse natural killer cells. Immunol Rev. 2006;214:47–55.

    Article  CAS  PubMed  Google Scholar 

  22. Meinhardt K, Kroeger I, Bauer R, Ganss F, Ovsiy I, Rothamer J, et al. Identification and characterization of the specific murine NK cell subset supporting graft-versus-leukemia- and reducing graft-versus-host-effects. Oncoimmunology. 2015;4:e981483.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  23. Zhang QF, Yin WW, Xia Y, Yi YY, He QF, Wang X, Ren H, Zhang DZ. Liver-infiltrating CD11b-CD27- NK subsets account for NK-cell dysfunction in patients with hepatocellular carcinoma and are associated with tumor progression. Cell Mol Immunol. 2016. doi:10.1038/cmi.2016.28.

  24. Renoux VM, Zriwil A, Peitzsch C, Michaelsson J, Friberg D, Soneji S, et al. Identification of a human natural killer cell lineage-restricted progenitor in fetal and adult tissues. Immunity. 2015;43:394–407.

    Article  CAS  PubMed  Google Scholar 

  25. Lopez-Verges S, Milush JM, Pandey S, York VA, Arakawa-Hoyt J, Pircher H, et al. CD57 defines a functionally distinct population of mature NK cells in the human CD56dimCD16+ NK-cell subset. Blood. 2010;116:3865–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Lopez-Verges S, Milush JM, Schwartz BS, Pando MJ, Jarjoura J, York VA, et al. Expansion of a unique CD57(+)NKG2Chi natural killer cell subset during acute human cytomegalovirus infection. Proc Natl Acad Sci U S A. 2011;108:14725–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Nielsen CM, White MJ, Goodier MR, Riley EM. Functional significance of CD57 expression on human NK cells and relevance to disease. Front Immunol. 2013;4:422.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  28. Chochi K, Ichikura T, Majima T, Kawabata T, Matsumoto A, Sugasawa H, et al. The increase of CD57+ T cells in the peripheral blood and their impaired immune functions in patients with advanced gastric cancer. Oncol Rep. 2003;10:1443–8.

    PubMed  Google Scholar 

  29. Kared H, Martelli S, Ng TP, Pender SL, Larbi A. CD57 in human natural killer cells and T-lymphocytes. Cancer Immunol Immunother. 2016;65:441–52.

    Article  CAS  PubMed  Google Scholar 

  30. Lv L, Pan K, Li XD, She KL, Zhao JJ, Wang W, et al. The accumulation and prognosis value of tumor infiltrating IL-17 producing cells in esophageal squamous cell carcinoma. PLoS One. 2011;6:e18219.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Ortac R, Aktas S, Diniz G, Erbay A, Vergin C. Prognostic role of natural killer cells in pediatric mixed cellularity and nodular sclerosing Hodgkin’s disease. Anal Quant Cytol Histol. 2002;24:249–53.

    PubMed  Google Scholar 

  32. Takanami I, Takeuchi K, Giga M. The prognostic value of natural killer cell infiltration in resected pulmonary adenocarcinoma. J Thorac Cardiovasc Surg. 2001;121:1058–63.

    Article  CAS  PubMed  Google Scholar 

  33. Villegas FR, Coca S, Villarrubia VG, Jimenez R, Chillon MJ, Jareno J, et al. Prognostic significance of tumor infiltrating natural killer cells subset CD57 in patients with squamous cell lung cancer. Lung Cancer. 2002;35:23–8.

    Article  PubMed  Google Scholar 

  34. Antonaci S, Polignano A, Ottolenghi A, Tortorella C, Schena FP. Redistribution of natural killer (NK) cell frequency and NK cytotoxic activity in primary IgA nephropathy. Cytobios. 1992;69:27–34.

    CAS  PubMed  Google Scholar 

  35. Batista MD, Ho EL, Kuebler PJ, Milush JM, Lanier LL, Kallas EG, et al. Skewed distribution of natural killer cells in psoriasis skin lesions. Exp Dermatol. 2013;22:64–6.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Cameron AL, Kirby B, Griffiths CE. Circulating natural killer cells in psoriasis. Br J Dermatol. 2003;149:160–4.

    Article  CAS  PubMed  Google Scholar 

  37. Matsumura G. Leu7 (HNK-1)-positive cells in peripheral blood and natural killer cell activity in patients with atopic dermatitis. Nihon Hifuka Gakkai Zasshi. 1990;100:57–62.

    CAS  PubMed  Google Scholar 

  38. Struyf NJ, Snoeck HW, Bridts CH, De Clerck LS, Stevens WJ. Natural killer cell activity in Sjogren’s syndrome and systemic lupus erythematosus: stimulation with interferons and interleukin-2 and correlation with immune complexes. Ann Rheum Dis. 1990;49:690–3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Wehrmann W, Reinhold U, Kukel S, Franke N, Uerlich M, Kreysel HW. Selective alterations in natural killer cell subsets in patients with atopic dermatitis. Int Arch Allergy Appl Immunol. 1990;92:318–22.

    Article  CAS  PubMed  Google Scholar 

  40. Cooper MA, Yokoyama WM. Memory-like responses of natural killer cells. Immunol Rev. 2010;235:297–305.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Erick TK, Brossay L. Phenotype and functions of conventional and non-conventional NK cells. Curr Opin Immunol. 2016;38:67–74.

    Article  CAS  PubMed  Google Scholar 

  42. Gan Y, Liu Q, Wu W, Yin JX, Bai XF, Shen R, et al. Ischemic neurons recruit natural killer cells that accelerate brain infarction. Proc Natl Acad Sci U S A. 2014;111:2704–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Nakayama M, Takeda K, Kawano M, Takai T, Ishii N, Ogasawara K. Natural killer (NK)-dendritic cell interactions generate MHC class II-dressed NK cells that regulate CD4+ T cells. Proc Natl Acad Sci U S A. 2011;108:18360–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Sun JC, Beilke JN, Bezman NA, Lanier LL. Homeostatic proliferation generates long-lived natural killer cells that respond against viral infection. J Exp Med. 2011;208:357–68.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Clinthorne JF, Beli E, Duriancik DM, Gardner EM. NK cell maturation and function in C57BL/6 mice are altered by caloric restriction. J Immunol. 2013;190:712–22.

    Article  CAS  PubMed  Google Scholar 

  46. Vosshenrich CA, Garcia-Ojeda ME, Samson-Villeger SI, Pasqualetto V, Enault L, Richard-Le Goff O, et al. A thymic pathway of mouse natural killer cell development characterized by expression of GATA-3 and CD127. Nat Immunol. 2006;7:1217–24.

    Article  CAS  PubMed  Google Scholar 

  47. Zhang J, Chen Z, Fritz JH, Rochman Y, Leonard WJ, Gommerman JL, et al. Unusual timing of CD127 expression by mouse uterine natural killer cells. J Leukoc Biol. 2012;91:417–26.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Montaldo E, Vacca P, Chiossone L, Croxatto D, Loiacono F, Martini S, et al. Unique Eomes(+) NK cell subsets are present in uterus and decidua during early pregnancy. Front Immunol. 2015;6:646.

    PubMed  Google Scholar 

  49. van der Molen RG, Schutten JH, van Cranenbroek B, ter Meer M, Donckers J, Scholten RR, et al. Menstrual blood closely resembles the uterine immune micro-environment and is clearly distinct from peripheral blood. Hum Reprod. 2014;29:303–14.

    Article  PubMed  CAS  Google Scholar 

  50. Daussy C, Faure F, Mayol K, Viel S, Gasteiger G, Charrier E, et al. T-bet and Eomes instruct the development of two distinct natural killer cell lineages in the liver and in the bone marrow. J Exp Med. 2014;211:563–77.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Gordon SM, Chaix J, Rupp LJ, Wu J, Madera S, Sun JC, et al. The transcription factors T-bet and Eomes control key checkpoints of natural killer cell maturation. Immunity. 2012;36:55–67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Marquardt N, Beziat V, Nystrom S, Hengst J, Ivarsson MA, Kekalainen E, et al. Cutting edge: identification and characterization of human intrahepatic CD49a+ NK cells. J Immunol. 2015;194:2467–71.

    Article  CAS  PubMed  Google Scholar 

  53. Tang L, Peng H, Zhou J, Chen Y, Wei H, Sun R, et al. Differential phenotypic and functional properties of liver-resident NK cells and mucosal ILC1s. J Autoimmun. 2016;67:29–35.

    Article  CAS  PubMed  Google Scholar 

  54. Carosella ED, Gregori S, Rouas-Freiss N, LeMaoult J, Menier C, Favier B. The role of HLA-G in immunity and hematopoiesis. Cell Mol Life Sci. 2011;68:353–68.

    Article  CAS  PubMed  Google Scholar 

  55. Cirulli V, Zalatan J, McMaster M, Prinsen R, Salomon DR, Ricordi C, et al. The class I HLA repertoire of pancreatic islets comprises the nonclassical class Ib antigen HLA-G. Diabetes. 2006;55:1214–22.

    Article  CAS  PubMed  Google Scholar 

  56. Crisa L, McMaster MT, Ishii JK, Fisher SJ, Salomon DR. Identification of a thymic epithelial cell subset sharing expression of the class Ib HLA-G molecule with fetal trophoblasts. J Exp Med. 1997;186:289–98.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Le Discorde M, Moreau P, Sabatier P, Legeais JM, Carosella ED. Expression of HLA-G in human cornea, an immune-privileged tissue. Hum Immunol. 2003;64:1039–44.

    Article  PubMed  CAS  Google Scholar 

  58. Mallet V, Fournel S, Schmitt C, Campan A, Lenfant F, Le Bouteiller P. Primary cultured human thymic epithelial cells express both membrane-bound and soluble HLA-G translated products. J Reprod Immunol. 1999;43:225–34.

    Article  CAS  PubMed  Google Scholar 

  59. Verloes A, Van de Velde H, LeMaoult J, Mateizel I, Cauffman G, Horn PA, et al. HLA-G expression in human embryonic stem cells and preimplantation embryos. J Immunol. 2011;186:2663–71.

    Article  CAS  PubMed  Google Scholar 

  60. Aslanidis S, Pyrpasopoulou A, Kontotasios K, Doumas S, Zamboulis C. Parvovirus B19 infection and systemic lupus erythematosus: activation of an aberrant pathway? Eur J Intern Med. 2008;19:314–8.

    Article  PubMed  Google Scholar 

  61. Goldstein BL, Chibnik LB, Karlson EW, Costenbader KH. Epstein-Barr virus serologic abnormalities and risk of rheumatoid arthritis among women. Autoimmunity. 2012;45:161–8.

    Article  CAS  PubMed  Google Scholar 

  62. Lin A, Xu H, Yan W. Modulation of HLA expression in human cytomegalovirus immune evasion. Cell Mol Immunol. 2007;4:91–8.

    PubMed  Google Scholar 

  63. Lisnic VJ, Krmpotic A, Jonjic S. Modulation of natural killer cell activity by viruses. Curr Opin Microbiol. 2010;13:530–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Liu Z, Winkler M, Biegalke B. Human cytomegalovirus: host immune modulation by the viral US3 gene. Int J Biochem Cell Biol. 2009;41:503–6.

    Article  CAS  PubMed  Google Scholar 

  65. Lodoen MB, Lanier LL. Viral modulation of NK cell immunity. Nat Rev Microbiol. 2005;3:59–69.

    Article  CAS  PubMed  Google Scholar 

  66. Loechelt BJ, Boulware D, Green M, Baden LR, Gottlieb P, Krause-Steinrauf H, et al. Epstein-Barr and other herpesvirus infections in patients with early onset type 1 diabetes treated with daclizumab and mycophenolate mofetil. Clin Infect Dis. 2013;56:248–54. This study provided supportive evidence for a strong association of some viral entities in patients with type 1 diabetes.

    Article  CAS  PubMed  Google Scholar 

  67. Ning S. Innate immune modulation in EBV infection. Herpesviridae. 2011;2:1.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Qin H, Lee IF, Panagiotopoulos C, Wang X, Chu AD, Utz PJ, et al. Natural killer cells from children with type 1 diabetes have defects in NKG2D-dependent function and signaling. Diabetes. 2011;60:857–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Herold KC, Huen A, Gould L, Traisman H, Rubenstein AH. Alterations in lymphocyte subpopulations in type 1 (insulin-dependent) diabetes mellitus: exploration of possible mechanisms and relationships to autoimmune phenomena. Diabetologia. 1984;27(Suppl):102–5.

    Article  PubMed  Google Scholar 

  70. Hussain MJ, Alviggi L, Millward BA, Leslie RD, Pyke DA, Vergani D. Evidence that the reduced number of natural killer cells in type 1 (insulin-dependent) diabetes may be genetically determined. Diabetologia. 1987;30:907–11.

    Article  CAS  PubMed  Google Scholar 

  71. Wilson RG, Anderson J, Shenton BK, White MD, Taylor RM, Proud G. Natural killer cells in insulin dependent diabetes mellitus. Br Med J (Clin Res Ed). 1986;293:244.

    Article  CAS  Google Scholar 

  72. Aarnisalo J, Veijola R, Vainionpaa R, Simell O, Knip M, Ilonen J. Cytomegalovirus infection in early infancy: risk of induction and progression of autoimmunity associated with type 1 diabetes. Diabetologia. 2008;51:769–72.

    Article  CAS  PubMed  Google Scholar 

  73. Richardson SJ, Willcox A, Bone AJ, Foulis AK, Morgan NG. The prevalence of enteroviral capsid protein vp1 immunostaining in pancreatic islets in human type 1 diabetes. Diabetologia. 2009;52:1143–51.

    Article  CAS  PubMed  Google Scholar 

  74. Oikarinen S, Tauriainen S, Hober D, Lucas B, Vazeou A, Sioofy-Khojine A, et al. Virus antibody survey in different European populations indicates risk association between coxsackievirus B1 and type 1 diabetes. Diabetes. 2014;63:655–62.

    Article  CAS  PubMed  Google Scholar 

  75. Bian X, Wallstrom G, Davis A, Wang J, Park J, Throop A, et al. Immunoproteomic profiling of antiviral antibodies in new-onset type 1 diabetes using protein arrays. Diabetes. 2016;65:285–96.

    CAS  PubMed  Google Scholar 

  76. Chistiakov DA. Interferon induced with helicase C domain 1 (IFIH1) and virus-induced autoimmunity: a review. Viral Immunol. 2010;23:3–15.

    Article  CAS  PubMed  Google Scholar 

  77. Nejentsev S, Walker N, Riches D, Egholm M, Todd JA. Rare variants of IFIH1, a gene implicated in antiviral responses, protect against type 1 diabetes. Science. 2009;324:387–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Smyth DJ, Cooper JD, Bailey R, Field S, Burren O, Smink LJ, et al. A genome-wide association study of nonsynonymous SNPs identifies a type 1 diabetes locus in the interferon-induced helicase (IFIH1) region. Nat Genet. 2006;38:617–9.

    Article  CAS  PubMed  Google Scholar 

  79. Colli ML, Moore F, Gurzov EN, Ortis F, Eizirik DL. MDA5 and PTPN2, two candidate genes for type 1 diabetes, modify pancreatic beta-cell responses to the viral by-product double-stranded RNA. Hum Mol Genet. 2010;19:135–46.

    Article  CAS  PubMed  Google Scholar 

  80. Dalbeth N, Callan MF. A subset of natural killer cells is greatly expanded within inflamed joints. Arthritis Rheum. 2002;46:1763–72.

    Article  PubMed  Google Scholar 

  81. Feuerer M, Shen Y, Littman DR, Benoist C, Mathis D. How punctual ablation of regulatory T cells unleashes an autoimmune lesion within the pancreatic islets. Immunity. 2009;31:654–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Garcia-Suarez J, Prieto A, Reyes E, Arribalzaga K, Perez-Machado MA, Lopez-Rubio M, et al. Persistent lymphocytosis of natural killer cells in autoimmune thrombocytopenic purpura (ATP) patients after splenectomy. Br J Haematol. 1995;89:653–5.

    Article  CAS  PubMed  Google Scholar 

  83. Yadav PK, Chen C, Liu Z. Potential role of NK cells in the pathogenesis of inflammatory bowel disease. J Biomed Biotechnol. 2011;2011:348530.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  84. Fort MM, Leach MW, Rennick DM. A role for NK cells as regulators of CD4+ T cells in a transfer model of colitis. J Immunol. 1998;161:3256–61.

    CAS  PubMed  Google Scholar 

  85. Matsumoto Y, Kohyama K, Aikawa Y, Shin T, Kawazoe Y, Suzuki Y, et al. Role of natural killer cells and TCR gamma delta T cells in acute autoimmune encephalomyelitis. Eur J Immunol. 1998;28:1681–8.

    Article  CAS  PubMed  Google Scholar 

  86. Shi FD, Wang HB, Li H, Hong S, Taniguchi M, Link H, et al. Natural killer cells determine the outcome of B cell-mediated autoimmunity. Nat Immunol. 2000;1:245–51.

    Article  CAS  PubMed  Google Scholar 

  87. Koevary SB. In vitro natural killer cell activity in the spontaneously diabetic BB/Wor rat: effects of serum on lysis of insulinoma cells. Diabetes Res. 1988;8:77–84.

    CAS  PubMed  Google Scholar 

  88. MacKay P, Jacobson J, Rabinovitch A. Spontaneous diabetes mellitus in the Bio-Breeding/Worcester rat. Evidence in vitro for natural killer cell lysis of islet cells. J Clin Invest. 1986;77:916–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Nakamura N, Woda BA, Tafuri A, Greiner DL, Reynolds CW, Ortaldo J, et al. Intrinsic cytotoxicity of natural killer cells to pancreatic islets in vitro. Diabetes. 1990;39:836–43.

    Article  CAS  PubMed  Google Scholar 

  90. Maruyama T, Watanabe K, Takei I, Kasuga A, Shimada A, Yanagawa T, et al. Anti-asialo GM1 antibody suppression of cyclophosphamide-induced diabetes in NOD mice. Diabetes Res. 1991;17:37–41.

    CAS  PubMed  Google Scholar 

  91. Maruyama T, Watanabe K, Yanagawa T, Kasatani T, Kasuga A, Shimada A, et al. The suppressive effect of anti-asialo GM1 antibody on low-dose streptozotocin-induced diabetes in CD-1 mice. Diabetes Res. 1991;16:171–5.

    CAS  PubMed  Google Scholar 

  92. Alba A, Planas R, Clemente X, Carrillo J, Ampudia R, Puertas MC, et al. Natural killer cells are required for accelerated type 1 diabetes driven by interferon-beta. Clin Exp Immunol. 2008;151:467–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Lee IF, Qin H, Priatel JJ, Tan R. Critical role for IFN-gamma in natural killer cell-mediated protection from diabetes. Eur J Immunol. 2008;38:82–9.

    Article  CAS  PubMed  Google Scholar 

  94. Ehlers M, Papewalis C, Stenzel W, Jacobs B, Meyer KL, Deenen R, et al. Immunoregulatory natural killer cells suppress autoimmunity by down-regulating antigen-specific CD8+ T cells in mice. Endocrinology. 2012;153:4367–79.

    Article  CAS  PubMed  Google Scholar 

  95. Beilke JN, Meagher CT, Hosiawa K, Champsaur M, Bluestone JA, Lanier LL. NK cells are not required for spontaneous autoimmune diabetes in NOD mice. PLoS One. 2012;7:e36011.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Ghadially H, Ohana M, Elboim M, Gazit R, Gur C, Nagler A, et al. NK cell receptor NKp46 regulates graft-versus-host disease. Cell Rep. 2014;7:1809–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Glasner A, Ghadially H, Gur C, Stanietsky N, Tsukerman P, Enk J, et al. Recognition and prevention of tumor metastasis by the NK receptor NKp46/NCR1. J Immunol. 2012;188:2509–15.

    Article  CAS  PubMed  Google Scholar 

  98. Gazit R, Gruda R, Elboim M, Arnon TI, Katz G, Achdout H, et al. Lethal influenza infection in the absence of the natural killer cell receptor gene Ncr1. Nat Immunol. 2006;7:517–23.

    Article  CAS  PubMed  Google Scholar 

  99. Bayer AL, Chirinos J, Cabello C, Yang J, Matsutani T, Malek TR, et al. Expansion of a restricted residual host Treg-cell repertoire is dependent on IL-2 following experimental autologous hematopoietic stem transplantation. Eur J Immunol. 2011;41:3467–78.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Bayer AL, Jones M, Chirinos J, de Armas L, Schreiber TH, Malek TR, et al. Host CD4+CD25+ T cells can expand and comprise a major component of the Treg compartment after experimental HCT. Blood. 2009;113:733–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Bayer AL, Malek TR, de la Barrera A, Cabello-Kindelan C. T regulatory cell adoptive therapy for tolerance induction in autoimmunity and transplantation. Am J Transplant. 2014;14:2432–3.

    Article  CAS  PubMed  Google Scholar 

  102. Cabello-Kindelan C, de la Barrera A, Malek TR, Bayer AL. In vivo environment necessary to support transplanted donor mouse T regulatory cells. Am J Transplant. 2014;14:1032–45.

    Article  CAS  PubMed  Google Scholar 

  103. Bayer AL, Pugliese A, Malek TR. The IL-2/IL-2R system: from basic science to therapeutic applications to enhance immune regulation. Immunol Res. 2013;57:197–209.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Sitrin J, Ring A, Garcia KC, Benoist C, Mathis D. Regulatory T cells control NK cells in an insulitic lesion by depriving them of IL-2. J Exp Med. 2013;210:1153–65. This study was a follow-up study that showed that NK cells are initiators of the diabetic lesion by stimulating CD4 T cells in NOD mice. Here in this study, IL-2 was identified as the critical link between Treg and NK cells with Treg cells predominantly controlled the availability of IL-2 in the microenvironment.

  105. Gasteiger G, Hemmers S, Bos PD, Sun JC, Rudensky AY. IL-2-dependent adaptive control of NK cell homeostasis. J Exp Med. 2013;210:1179–87. This study supported findings for the critical link of IL-2 availability in the absence of Treg cells in the microenvironment for NK activation and IFNγ production.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Denny P, Lord CJ, Hill NJ, Goy JV, Levy ER, Podolin PL, et al. Mapping of the IDDM locus Idd3 to a 0.35-cM interval containing the interleukin-2 gene. Diabetes. 1997;46:695–700.

    Article  CAS  PubMed  Google Scholar 

  107. Setoguchi R, Hori S, Takahashi T, Sakaguchi S. Homeostatic maintenance of natural Foxp3+CD25+CD4+ regulatory T cells by interleukin (IL)-2 and induction of autoimmune disease by IL-2 neutralization. J Exp Med. 2005;201:723–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Yamanouchi J, Rainbow D, Serra P, Howlett S, Hunter K, Garner VE, et al. Interleukin-2 gene variation impairs regulatory T cell function and causes autoimmunity. Nat Genet. 2007;39:329–37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Grinberg-Bleyer Y, Baeyens A, You S, Elhage R, Fourcade G, Gregoire S, et al. IL-2 reverses established type 1 diabetes in NOD mice by a local effect on pancreatic regulatory T cells. J Exp Med. 2010;207:1871–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Tang Q, Adams JY, Penaranda C, Melli K, Piaggio E, Sgouroudis E, et al. Central role of defective interleukin-2 production in the triggering of islet autoimmune destruction. Immunity. 2008;28:687–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Xia J, Liu W, Hu B, Tian Z, Yang Y. IL-15 promotes regulatory T cell function and protects against diabetes development in NK-depleted NOD mice. Clin Immunol. 2010;134:130–9.

    Article  CAS  PubMed  Google Scholar 

  112. Baeyens A, Perol L, Fourcade G, Cagnard N, Carpentier W, Woytschak J, et al. Limitations of IL-2 and rapamycin in immunotherapy of type 1 diabetes. Diabetes. 2013;62:3120–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Skyler JS. Struggles with clinical translation of immune intervention trials. Diabetes Care. 2014;37:1173–5.

    Article  CAS  PubMed  Google Scholar 

  114. Hagopian W, Ferry Jr RJ, Sherry N, Carlin D, Bonvini E, Johnson S, et al. Teplizumab preserves C-peptide in recent-onset type 1 diabetes: two-year results from the randomized, placebo-controlled Protege trial. Diabetes. 2013;62:3901–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Laughlin E, Burke G, Pugliese A, Falk B, Nepom G. Recurrence of autoreactive antigen-specific CD4+ T cells in autoimmune diabetes after pancreas transplantation. Clin Immunol. 2008;128:23–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Martins L, Malheiro J, Henriques AC, Dias L, Dores J, Oliveira F, et al. Pancreas-kidney transplantation and the evolution of pancreatic autoantibodies. Transplant Proc. 2009;41:913–5.

    Article  CAS  PubMed  Google Scholar 

  117. Vendrame F, Pileggi A, Laughlin E, Allende G, Martin-Pagola A, Molano RD, et al. Recurrence of type 1 diabetes after simultaneous pancreas-kidney transplantation, despite immunosuppression, is associated with autoantibodies and pathogenic autoreactive CD4 T-cells. Diabetes. 2010;59:947–57.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Boettler T, von Herrath M. Immunotherapy of type 1 diabetes—how to rationally prioritize combination therapies in T1D. Int Immunopharmacol. 2010;10(12):1491–5.

    Article  CAS  PubMed  Google Scholar 

  119. Bresson D, von Herrath M. Immunotherapy for the prevention and treatment of type 1 diabetes: optimizing the path from bench to bedside. Diabetes Care. 2009;32:1753–68.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Matthews JB, Staeva TP, Bernstein PL, Peakman M, von Herrath M. Developing combination immunotherapies for type 1 diabetes: recommendations from the ITN-JDRF Type 1 Diabetes Combination Therapy Assessment Group. Clin Exp Immunol. 2010;160:176–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Diabetes Research Institute, University of Miami Miller School of Medicine, Miami, FL, 33136, USA

    Chris Fraker & Allison L. Bayer

  2. Department of Microbiology and Immunology, University of Miami Miller School of Medicine, Miami, FL, 33136, USA

    Allison L. Bayer

Authors
  1. Chris Fraker
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Allison L. Bayer
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Allison L. Bayer.

Ethics declarations

Conflict of Interest

Chris Fraker and Allison L. Bayer declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Additional information

This article is part of the Topical Collection on Pathogenesis of Type 1 Diabetes

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Fraker, C., Bayer, A.L. The Expanding Role of Natural Killer Cells in Type 1 Diabetes and Immunotherapy. Curr Diab Rep 16, 109 (2016). https://doi.org/10.1007/s11892-016-0806-7

Download citation

  • Published:

  • DOI: https://doi.org/10.1007/s11892-016-0806-7

Keywords

Search

Navigation