Cellular and Molecular Life Sciences

, Volume 70, Issue 24, pp 4711–4727 | Cite as

Invariant natural killer T cells in adipose tissue: novel regulators of immune-mediated metabolic disease

  • M. Rakhshandehroo
  • E. Kalkhoven
  • M. Boes


Adipose tissue (AT) represents a microenvironment where intersection takes place between immune processes and metabolic pathways. A variety of immune cells have been characterized in AT over the past decades, with the most recent addition of invariant natural killer T (iNKT) cells. As members of the T cell family, iNKT cells represent a subset that exhibits both innate and adaptive characteristics and directs ensuing immune responses. In disease conditions, iNKT cells have established roles that include disorders in the autoimmune spectrum in malignancies and infectious diseases. Recent work supports a role for iNKT cells in the maintenance of AT homeostasis through both immune and metabolic pathways. The deficiency of iNKT cells can result in AT metabolic disruptions and insulin resistance. In this review, we summarize recent work on iNKT cells in immune regulation, with an emphasis on AT-resident iNKT cells, and identify the potential mechanisms by which adipocytes can mediate iNKT cell activity.


Invariant natural killer T cells Insulin resistance Obesity Type II diabetes Adipose tissue Immune regulation 



The authors would like to thank Dr. R. Stienstra for providing pictures presented in Fig. 1. This work was supported by the Dutch Technology Foundation STW, which is the applied science division of NWO, and the Technology Programme of the Ministry of Economic affairs and by an EFSD/Lilly research grant.


  1. 1.
    Shu CJ, Benoist C, Mathis D (2012) The immune system’s involvement in obesity-driven type 2 diabetes. Semin Immunol 24(6):436–442. doi: 10.1016/j.smim.2012.12.001 PubMedGoogle Scholar
  2. 2.
    Talukdar S, da Oh Y, Bandyopadhyay G, Li D, Xu J, McNelis J, Lu M, Li P, Yan Q, Zhu Y, Ofrecio J, Lin M, Brenner MB, Olefsky JM (2012) Neutrophils mediate insulin resistance in mice fed a high-fat diet through secreted elastase. Nat Med 18(9):1407–1412. doi: 10.1038/nm.2885 PubMedGoogle Scholar
  3. 3.
    Liu J, Divoux A, Sun J, Zhang J, Clement K, Glickman JN, Sukhova GK, Wolters PJ, Du J, Gorgun CZ, Doria A, Libby P, Blumberg RS, Kahn BB, Hotamisligil GS, Shi GP (2009) Genetic deficiency and pharmacological stabilization of mast cells reduce diet-induced obesity and diabetes in mice. Nat Med 15(8):940–945. doi: 10.1038/nm.1994 PubMedGoogle Scholar
  4. 4.
    Winer DA, Winer S, Shen L, Wadia PP, Yantha J, Paltser G, Tsui H, Wu P, Davidson MG, Alonso MN, Leong HX, Glassford A, Caimol M, Kenkel JA, Tedder TF, McLaughlin T, Miklos DB, Dosch HM, Engleman EG (2011) B cells promote insulin resistance through modulation of T cells and production of pathogenic IgG antibodies. Nat Med 17(5):610–617. doi: 10.1038/nm.2353 PubMedGoogle Scholar
  5. 5.
    Nishimura S, Manabe I, Nagasaki M, Eto K, Yamashita H, Ohsugi M, Otsu M, Hara K, Ueki K, Sugiura S, Yoshimura K, Kadowaki T, Nagai R (2009) CD8+ effector T cells contribute to macrophage recruitment and adipose tissue inflammation in obesity. Nat Med 15(8):914–920. doi: 10.1038/nm.1964 PubMedGoogle Scholar
  6. 6.
    Winer S, Chan Y, Paltser G, Truong D, Tsui H, Bahrami J, Dorfman R, Wang Y, Zielenski J, Mastronardi F, Maezawa Y, Drucker DJ, Engleman E, Winer D, Dosch HM (2009) Normalization of obesity-associated insulin resistance through immunotherapy. Nat Med 15(8):921–929. doi: 10.1038/nm.2001 PubMedGoogle Scholar
  7. 7.
    Molofsky AB, Nussbaum JC, Liang HE, Van Dyken SJ, Cheng LE, Mohapatra A, Chawla A, Locksley RM (2013) Innate lymphoid type 2 cells sustain visceral adipose tissue eosinophils and alternatively activated macrophages. J Exp Med 210(3):535–549. doi: 10.1084/jem.20121964 PubMedGoogle Scholar
  8. 8.
    Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel RL, Ferrante AW Jr (2003) Obesity is associated with macrophage accumulation in adipose tissue. J Clin Investig 112(12):1796–1808. doi: 10.1172/JCI19246 PubMedGoogle Scholar
  9. 9.
    Xu H, Barnes GT, Yang Q, Tan G, Yang D, Chou CJ, Sole J, Nichols A, Ross JS, Tartaglia LA, Chen H (2003) Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J Clin Investig 112(12):1821–1830. doi: 10.1172/JCI19451 PubMedGoogle Scholar
  10. 10.
    Chawla A, Nguyen KD, Goh YP (2011) Macrophage-mediated inflammation in metabolic disease. Nat Rev Immunol 11(11):738–749. doi: 10.1038/nri3071 PubMedGoogle Scholar
  11. 11.
    Donath MY, Shoelson SE (2011) Type 2 diabetes as an inflammatory disease. Nat Rev Immunol 11(2):98–107. doi: 10.1038/nri2925 PubMedGoogle Scholar
  12. 12.
    Johnson AM, Olefsky JM (2013) The origins and drivers of insulin resistance. Cell 152(4):673–684. doi: 10.1016/j.cell.2013.01.041 PubMedGoogle Scholar
  13. 13.
    Schipper HS, Prakken B, Kalkhoven E, Boes M (2012) Adipose tissue-resident immune cells: key players in immunometabolism. Trends Endocrinol Metab: TEM 23(8):407–415. doi: 10.1016/j.tem.2012.05.011 PubMedGoogle Scholar
  14. 14.
    Hotamisligil GS, Shargill NS, Spiegelman BM (1993) Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance. Science 259(5091):87–91PubMedGoogle Scholar
  15. 15.
    Hotamisligil GS, Peraldi P, Budavari A, Ellis R, White MF, Spiegelman BM (1996) IRS-1-mediated inhibition of insulin receptor tyrosine kinase activity in TNF-alpha- and obesity-induced insulin resistance. Science 271(5249):665–668PubMedGoogle Scholar
  16. 16.
    Konner AC, Bruning JC (2011) Toll-like receptors: linking inflammation to metabolism. Trends Endocrinol Metab: TEM 22(1):16–23. doi: 10.1016/j.tem.2010.08.007 PubMedGoogle Scholar
  17. 17.
    Saltiel AR (2012) Insulin resistance in the defense against obesity. Cell Metab 15(6):798–804. doi: 10.1016/j.cmet.2012.03.001 PubMedGoogle Scholar
  18. 18.
    Lumeng CN, Bodzin JL, Saltiel AR (2007) Obesity induces a phenotypic switch in adipose tissue macrophage polarization. J Clin Investig 117(1):175–184. doi: 10.1172/JCI29881 PubMedGoogle Scholar
  19. 19.
    Dalmas E, Clement K, Guerre-Millo M (2011) Defining macrophage phenotype and function in adipose tissue. Trends Immunol 32(7):307–314. doi: 10.1016/ PubMedGoogle Scholar
  20. 20.
    Bendelac A, Savage PB, Teyton L (2007) The biology of NKT cells. Annu Rev Immunol 25:297–336. doi: 10.1146/annurev.immunol.25.022106.141711 PubMedGoogle Scholar
  21. 21.
    Godfrey DI, MacDonald HR, Kronenberg M, Smyth MJ, Van Kaer L (2004) NKT cells: what’s in a name? Nat Rev Immunol 4(3):231–237. doi: 10.1038/nri1309 PubMedGoogle Scholar
  22. 22.
    Sharif S, Arreaza GA, Zucker P, Mi QS, Sondhi J, Naidenko OV, Kronenberg M, Koezuka Y, Delovitch TL, Gombert JM, Leite-De-Moraes M, Gouarin C, Zhu R, Hameg A, Nakayama T, Taniguchi M, Lepault F, Lehuen A, Bach JF, Herbelin A (2001) Activation of natural killer T cells by alpha-galactosylceramide treatment prevents the onset and recurrence of autoimmune type 1 diabetes. Nat Med 7(9):1057–1062. doi: 10.1038/nm0901-1057 PubMedGoogle Scholar
  23. 23.
    Sprengers D, Sille FC, Derkow K, Besra GS, Janssen HL, Schott E, Boes M (2008) Critical role for CD1d-restricted invariant NKT cells in stimulating intrahepatic CD8 T-cell responses to liver antigen. Gastroenterology 134(7):2132–2143. doi: 10.1053/j.gastro.2008.02.037 PubMedGoogle Scholar
  24. 24.
    Swann JB, Coquet JM, Smyth MJ, Godfrey DI (2007) CD1-restricted T cells and tumor immunity. Curr Top Microbiol Immunol 314:293–323PubMedGoogle Scholar
  25. 25.
    Wu L, Van Kaer L (2009) Natural killer T cells and autoimmune disease. Curr Mol Med 9(1):4–14PubMedGoogle Scholar
  26. 26.
    Beckman EM, Porcelli SA, Morita CT, Behar SM, Furlong ST, Brenner MB (1994) Recognition of a lipid antigen by CD1-restricted alpha beta+ T cells. Nature 372(6507):691–694. doi: 10.1038/372691a0 PubMedGoogle Scholar
  27. 27.
    Joyce S, Negishi I, Boesteanu A, DeSilva AD, Sharma P, Chorney MJ, Loh DY, Van Kaer L (1996) Expansion of natural (NK1+) T cells that express alpha beta T cell receptors in transporters associated with antigen presentation-1 null and thymus leukemia antigen positive mice. J Exp Med 184(4):1579–1584PubMedGoogle Scholar
  28. 28.
    Exley M, Garcia J, Balk SP, Porcelli S (1997) Requirements for CD1d recognition by human invariant Valpha24+ CD4−CD8− T cells. J Exp Med 186(1):109–120PubMedGoogle Scholar
  29. 29.
    Kawano T, Cui J, Koezuka Y, Toura I, Kaneko Y, Motoki K, Ueno H, Nakagawa R, Sato H, Kondo E, Koseki H, Taniguchi M (1997) CD1d-restricted and TCR-mediated activation of valpha14 NKT cells by glycosylceramides. Science 278(5343):1626–1629PubMedGoogle Scholar
  30. 30.
    Exley M, Porcelli S, Furman M, Garcia J, Balk S (1998) CD161 (NKR-P1A) costimulation of CD1d-dependent activation of human T cells expressing invariant V alpha 24J alpha Q T cell receptor alpha chains. J Exp Med 188(5):867–876PubMedGoogle Scholar
  31. 31.
    Brossay L, Chioda M, Burdin N, Koezuka Y, Casorati G, Dellabona P, Kronenberg M (1998) CD1d-mediated recognition of an alpha-galactosylceramide by natural killer T cells is highly conserved through mammalian evolution. J Exp Med 188(8):1521–1528PubMedGoogle Scholar
  32. 32.
    Hammond KJ, Pelikan SB, Crowe NY, Randle-Barrett E, Nakayama T, Taniguchi M, Smyth MJ, van Driel IR, Scollay R, Baxter AG, Godfrey DI (1999) NKT cells are phenotypically and functionally diverse. Eur J Immunol 29(11):3768–3781. doi: 10.1002/(SICI)1521-4141(199911)29:11<3768:AID-IMMU3768>3.0.CO;2-G PubMedGoogle Scholar
  33. 33.
    Eberl G, MacDonald HR (1998) Rapid death and regeneration of NKT cells in anti-CD3epsilon- or IL-12-treated mice: a major role for bone marrow in NKT cell homeostasis. Immunity 9(3):345–353PubMedGoogle Scholar
  34. 34.
    Godfrey DI, Stankovic S, Baxter AG (2010) Raising the NKT cell family. Nat Immunol 11(3):197–206. doi: 10.1038/ni.1841 PubMedGoogle Scholar
  35. 35.
    Boes M, Stoppelenburg AJ, Sille FC (2009) Endosomal processing for antigen presentation mediated by CD1 and class I major histocompatibility complex: roads to display or destruction. Immunology 127(2):163–170. doi: 10.1111/j.1365-2567.2009.03078.x PubMedGoogle Scholar
  36. 36.
    Girardi E, Maricic I, Wang J, Mac TT, Iyer P, Kumar V, Zajonc DM (2012) Type II natural killer T cells use features of both innate-like and conventional T cells to recognize sulfatide self-antigens. Nat Immunol 13(9):851–856. doi: 10.1038/ni.2371 PubMedGoogle Scholar
  37. 37.
    Jahng A, Maricic I, Aguilera C, Cardell S, Halder RC, Kumar V (2004) Prevention of autoimmunity by targeting a distinct, noninvariant CD1d-reactive T cell population reactive to sulfatide. J Exp Med 199(7):947–957. doi: 10.1084/jem.20031389 PubMedGoogle Scholar
  38. 38.
    Arrenberg P, Maricic I, Kumar V (2011) Sulfatide-mediated activation of type II natural killer T cells prevents hepatic ischemic reperfusion injury in mice. Gastroenterology 140(2):646–655. doi: 10.1053/j.gastro.2010.10.003 PubMedGoogle Scholar
  39. 39.
    Satoh M, Andoh Y, Clingan CS, Ogura H, Fujii S, Eshima K, Nakayama T, Taniguchi M, Hirata N, Ishimori N, Tsutsui H, Onoe K, Iwabuchi K (2012) Type II NKT cells stimulate diet-induced obesity by mediating adipose tissue inflammation, steatohepatitis and insulin resistance. PLoS One 7(2):e30568. doi: 10.1371/journal.pone.0030568 PubMedGoogle Scholar
  40. 40.
    Benlagha K, Wei DG, Veiga J, Teyton L, Bendelac A (2005) Characterization of the early stages of thymic NKT cell development. J Exp Med 202(4):485–492. doi: 10.1084/jem.20050456 PubMedGoogle Scholar
  41. 41.
    Gapin L, Matsuda JL, Surh CD, Kronenberg M (2001) NKT cells derive from double-positive thymocytes that are positively selected by CD1d. Nat Immunol 2(10):971–978. doi: 10.1038/ni710 PubMedGoogle Scholar
  42. 42.
    McNab FW, Berzins SP, Pellicci DG, Kyparissoudis K, Field K, Smyth MJ, Godfrey DI (2005) The influence of CD1d in postselection NKT cell maturation and homeostasis. J Immunol 175(6):3762–3768PubMedGoogle Scholar
  43. 43.
    Sille FC, Martin C, Jayaraman P, Rothchild A, Besra GS, Behar SM, Boes M (2011) Critical role for invariant chain in CD1d-mediated selection and maturation of Valpha14-invariant NKT cells. Immunol Lett 139(1–2):33–41. doi: 10.1016/j.imlet.2011.04.012 PubMedGoogle Scholar
  44. 44.
    Sille FC, Boxem M, Sprengers D, Veerapen N, Besra G, Boes M (2009) Distinct requirements for CD1d intracellular transport for development of V(alpha)14 iNKT cells. J Immunol 183(3):1780–1788. doi: 10.4049/jimmunol.0901354 PubMedGoogle Scholar
  45. 45.
    Wei DG, Lee H, Park SH, Beaudoin L, Teyton L, Lehuen A, Bendelac A (2005) Expansion and long-range differentiation of the NKT cell lineage in mice expressing CD1d exclusively on cortical thymocytes. J Exp Med 202(2):239–248. doi: 10.1084/jem.20050413 PubMedGoogle Scholar
  46. 46.
    Benlagha K, Kyin T, Beavis A, Teyton L, Bendelac A (2002) A thymic precursor to the NK T cell lineage. Science 296(5567):553–555PubMedGoogle Scholar
  47. 47.
    Pellicci DG, Hammond KJ, Uldrich AP, Baxter AG, Smyth MJ, Godfrey DI (2002) A natural killer T (NKT) cell developmental pathway involving a thymus-dependent NK1.1(−)CD4(+) CD1d-dependent precursor stage. J Exp Med 195(7):835–844PubMedGoogle Scholar
  48. 48.
    Matsuda JL, Mallevaey T, Scott-Browne J, Gapin L (2008) CD1d-restricted iNKT cells, the ‘Swiss-Army knife’ of the immune system. Curr Opin Immunol 20(3):358–368. doi: 10.1016/j.coi.2008.03.018 PubMedGoogle Scholar
  49. 49.
    Godfrey DI, Kronenberg M (2004) Going both ways: immune regulation via CD1d-dependent NKT cells. J Clin Investig 114(10):1379–1388. doi: 10.1172/JCI23594 PubMedGoogle Scholar
  50. 50.
    Morita M, Motoki K, Akimoto K, Natori T, Sakai T, Sawa E, Yamaji K, Koezuka Y, Kobayashi E, Fukushima H (1995) Structure-activity relationship of alpha-galactosylceramides against B16-bearing mice. J Med Chem 38(12):2176–2187PubMedGoogle Scholar
  51. 51.
    Kinjo Y, Wu D, Kim G, Xing GW, Poles MA, Ho DD, Tsuji M, Kawahara K, Wong CH, Kronenberg M (2005) Recognition of bacterial glycosphingolipids by natural killer T cells. Nature 434(7032):520–525. doi: 10.1038/nature03407 PubMedGoogle Scholar
  52. 52.
    Mattner J, Debord KL, Ismail N, Goff RD, Cantu C 3rd, Zhou D, Saint-Mezard P, Wang V, Gao Y, Yin N, Hoebe K, Schneewind O, Walker D, Beutler B, Teyton L, Savage PB, Bendelac A (2005) Exogenous and endogenous glycolipid antigens activate NKT cells during microbial infections. Nature 434(7032):525–529. doi: 10.1038/nature03408 PubMedGoogle Scholar
  53. 53.
    Sriram V, Du W, Gervay-Hague J, Brutkiewicz RR (2005) Cell wall glycosphingolipids of Sphingomonas paucimobilis are CD1d-specific ligands for NKT cells. Eur J Immunol 35(6):1692–1701. doi: 10.1002/eji.200526157 PubMedGoogle Scholar
  54. 54.
    Kinjo Y, Tupin E, Wu D, Fujio M, Garcia-Navarro R, Benhnia MR, Zajonc DM, Ben-Menachem G, Ainge GD, Painter GF, Khurana A, Hoebe K, Behar SM, Beutler B, Wilson IA, Tsuji M, Sellati TJ, Wong CH, Kronenberg M (2006) Natural killer T cells recognize diacylglycerol antigens from pathogenic bacteria. Nat Immunol 7(9):978–986. doi: 10.1038/ni1380 PubMedGoogle Scholar
  55. 55.
    Pei B, Vela JL, Zajonc D, Kronenberg M (2012) Interplay between carbohydrate and lipid in recognition of glycolipid antigens by natural killer T cells. Ann N Y Acad Sci 1253:68–79. doi: 10.1111/j.1749-6632.2011.06435.x PubMedGoogle Scholar
  56. 56.
    Brigl M, Bry L, Kent SC, Gumperz JE, Brenner MB (2003) Mechanism of CD1d-restricted natural killer T cell activation during microbial infection. Nat Immunol 4(12):1230–1237. doi: 10.1038/ni1002 PubMedGoogle Scholar
  57. 57.
    Nagarajan NA, Kronenberg M (2007) Invariant NKT cells amplify the innate immune response to lipopolysaccharide. J Immunol 178(5):2706–2713PubMedGoogle Scholar
  58. 58.
    Skold M, Xiong X, Illarionov PA, Besra GS, Behar SM (2005) Interplay of cytokines and microbial signals in regulation of CD1d expression and NKT cell activation. J Immunol 175(6):3584–3593PubMedGoogle Scholar
  59. 59.
    Salio M, Speak AO, Shepherd D, Polzella P, Illarionov PA, Veerapen N, Besra GS, Platt FM, Cerundolo V (2007) Modulation of human natural killer T cell ligands on TLR-mediated antigen-presenting cell activation. Proc Natl Acad Sci USA 104(51):20490–20495. doi: 10.1073/pnas.0710145104 PubMedGoogle Scholar
  60. 60.
    Paget C, Mallevaey T, Speak AO, Torres D, Fontaine J, Sheehan KC, Capron M, Ryffel B, Faveeuw C, Leite de Moraes M, Platt F, Trottein F (2007) Activation of invariant NKT cells by toll-like receptor 9-stimulated dendritic cells requires type I interferon and charged glycosphingolipids. Immunity 27(4):597–609. doi: 10.1016/j.immuni.2007.08.017 PubMedGoogle Scholar
  61. 61.
    Leite-De-Moraes MC, Hameg A, Arnould A, Machavoine F, Koezuka Y, Schneider E, Herbelin A, Dy M (1999) A distinct IL-18-induced pathway to fully activate NK T lymphocytes independently from TCR engagement. J Immunol 163(11):5871–5876PubMedGoogle Scholar
  62. 62.
    Tyznik AJ, Tupin E, Nagarajan NA, Her MJ, Benedict CA, Kronenberg M (2008) Cutting edge: the mechanism of invariant NKT cell responses to viral danger signals. J Immunol 181(7):4452–4456PubMedGoogle Scholar
  63. 63.
    Lee PT, Benlagha K, Teyton L, Bendelac A (2002) Distinct functional lineages of human V(alpha)24 natural killer T cells. J Exp Med 195(5):637–641PubMedGoogle Scholar
  64. 64.
    Gumperz JE, Miyake S, Yamamura T, Brenner MB (2002) Functionally distinct subsets of CD1d-restricted natural killer T cells revealed by CD1d tetramer staining. J Exp Med 195(5):625–636PubMedGoogle Scholar
  65. 65.
    Matsuda JL, Naidenko OV, Gapin L, Nakayama T, Taniguchi M, Wang CR, Koezuka Y, Kronenberg M (2000) Tracking the response of natural killer T cells to a glycolipid antigen using CD1d tetramers. J Exp Med 192(5):741–754PubMedGoogle Scholar
  66. 66.
    Matsuda JL, Gapin L, Baron JL, Sidobre S, Stetson DB, Mohrs M, Locksley RM, Kronenberg M (2003) Mouse V alpha 14i natural killer T cells are resistant to cytokine polarization in vivo. Proc Natl Acad Sci USA 100(14):8395–8400. doi: 10.1073/pnas.1332805100 PubMedGoogle Scholar
  67. 67.
    Crowe NY, Uldrich AP, Kyparissoudis K, Hammond KJ, Hayakawa Y, Sidobre S, Keating R, Kronenberg M, Smyth MJ, Godfrey DI (2003) Glycolipid antigen drives rapid expansion and sustained cytokine production by NK T cells. J Immunol 171(8):4020–4027PubMedGoogle Scholar
  68. 68.
    Wun KS, Cameron G, Patel O, Pang SS, Pellicci DG, Sullivan LC, Keshipeddy S, Young MH, Uldrich AP, Thakur MS, Richardson SK, Howell AR, Illarionov PA, Brooks AG, Besra GS, McCluskey J, Gapin L, Porcelli SA, Godfrey DI, Rossjohn J (2011) A molecular basis for the exquisite CD1d-restricted antigen specificity and functional responses of natural killer T cells. Immunity 34(3):327–339. doi: 10.1016/j.immuni.2011.02.001 PubMedGoogle Scholar
  69. 69.
    Tyznik AJ, Farber E, Girardi E, Birkholz A, Li Y, Chitale S, So R, Arora P, Khurana A, Wang J, Porcelli SA, Zajonc DM, Kronenberg M, Howell AR (2011) Glycolipids that elicit IFN-gamma-biased responses from natural killer T cells. Chem Biol 18(12):1620–1630. doi: 10.1016/j.chembiol.2011.10.015 PubMedGoogle Scholar
  70. 70.
    Wun KS, Ross F, Patel O, Besra GS, Porcelli SA, Richardson SK, Keshipeddy S, Howell AR, Godfrey DI, Rossjohn J (2012) Human and mouse type I natural killer T cell antigen receptors exhibit different fine specificities for CD1d-antigen complex. J Biol Chem 287(46):39139–39148. doi: 10.1074/jbc.M112.412320 PubMedGoogle Scholar
  71. 71.
    Mukherjee S, Soe TT, Maxfield FR (1999) Endocytic sorting of lipid analogues differing solely in the chemistry of their hydrophobic tails. J Cell Biol 144(6):1271–1284PubMedGoogle Scholar
  72. 72.
    Barral DC, Brenner MB (2007) CD1 antigen presentation: how it works. Nat Rev Immunol 7(12):929–941. doi: 10.1038/nri2191 PubMedGoogle Scholar
  73. 73.
    Bai L, Sagiv Y, Liu Y, Freigang S, Yu KO, Teyton L, Porcelli SA, Savage PB, Bendelac A (2009) Lysosomal recycling terminates CD1d-mediated presentation of short and polyunsaturated variants of the NKT cell lipid antigen alphaGalCer. Proc Natl Acad Sci USA 106(25):10254–10259. doi: 10.1073/pnas.0901228106 PubMedGoogle Scholar
  74. 74.
    Schipper HS, Rakhshandehroo M, van de Graaf SF, Venken K, Koppen A, Stienstra R, Prop S, Meerding J, Hamers N, Besra G, Boon L, Nieuwenhuis EE, Elewaut D, Prakken B, Kersten S, Boes M, Kalkhoven E (2012) Natural killer T cells in adipose tissue prevent insulin resistance. J Clin Investig 122(9):3343–3354. doi: 10.1172/JCI62739 PubMedGoogle Scholar
  75. 75.
    Huh JY, Kim JI, Park YJ, Hwang IJ, Lee YS, Sohn JH, Lee SK, Alfadda AA, Kim SS, Choi SH, Lee DS, Park SH, Seong RH, Choi CS, Kim JB (2013) A Novel function of adipocytes in lipid antigen presentation to iNKT cells. Mol Cell Biol 33(2):328–339. doi: 10.1128/MCB.00552-12 PubMedGoogle Scholar
  76. 76.
    Sille FC, Martin C, Jayaraman P, Rothchild A, Fortune S, Besra GS, Behar SM, Boes M (2011) Requirement for invariant chain in macrophages for Mycobacterium tuberculosis replication and CD1d antigen presentation. Infect Immun 79(8):3053–3063. doi: 10.1128/IAI.01108-10 PubMedGoogle Scholar
  77. 77.
    Kang SJ, Cresswell P (2002) Regulation of intracellular trafficking of human CD1d by association with MHC class II molecules. EMBO J 21(7):1650–1660. doi: 10.1093/emboj/21.7.1650 PubMedGoogle Scholar
  78. 78.
    Jayawardena-Wolf J, Benlagha K, Chiu YH, Mehr R, Bendelac A (2001) CD1d endosomal trafficking is independently regulated by an intrinsic CD1d-encoded tyrosine motif and by the invariant chain. Immunity 15(6):897–908PubMedGoogle Scholar
  79. 79.
    Chiu YH, Park SH, Benlagha K, Forestier C, Jayawardena-Wolf J, Savage PB, Teyton L, Bendelac A (2002) Multiple defects in antigen presentation and T cell development by mice expressing cytoplasmic tail-truncated CD1d. Nat Immunol 3(1):55–60. doi: 10.1038/ni740 PubMedGoogle Scholar
  80. 80.
    Elewaut D, Lawton AP, Nagarajan NA, Maverakis E, Khurana A, Honing S, Benedict CA, Sercarz E, Bakke O, Kronenberg M, Prigozy TI (2003) The adaptor protein AP-3 is required for CD1d-mediated antigen presentation of glycosphingolipids and development of Valpha14i NKT cells. J Exp Med 198(8):1133–1146. doi: 10.1084/jem.20030143 PubMedGoogle Scholar
  81. 81.
    Sugita M, Cao X, Watts GF, Rogers RA, Bonifacino JS, Brenner MB (2002) Failure of trafficking and antigen presentation by CD1 in AP-3-deficient cells. Immunity 16(5):697–706PubMedGoogle Scholar
  82. 82.
    Briken V, Jackman RM, Dasgupta S, Hoening S, Porcelli SA (2002) Intracellular trafficking pathway of newly synthesized CD1b molecules. The EMBO journal 21(4):825–834. doi: 10.1093/emboj/21.4.825 PubMedGoogle Scholar
  83. 83.
    Odyniec AN, Barral DC, Garg S, Tatituri RV, Besra GS, Brenner MB (2010) Regulation of CD1 antigen-presenting complex stability. J Biol Chem 285(16):11937–11947. doi: 10.1074/jbc.M109.077933 PubMedGoogle Scholar
  84. 84.
    Moody DB, Zajonc DM, Wilson IA (2005) Anatomy of CD1-lipid antigen complexes. Nat Rev Immunol 5(5):387–399. doi: 10.1038/nri1605 PubMedGoogle Scholar
  85. 85.
    Cohen NR, Garg S, Brenner MB (2009) Antigen presentation by CD1 lipids, T cells, and NKT cells in microbial immunity. Adv Immunol 102:1–94. doi: 10.1016/S0065-2776(09)01201-2 PubMedGoogle Scholar
  86. 86.
    Godfrey DI, Pellicci DG, Patel O, Kjer-Nielsen L, McCluskey J, Rossjohn J (2010) Antigen recognition by CD1d-restricted NKT T cell receptors. Semin Immunol 22(2):61–67. doi: 10.1016/j.smim.2009.10.004 PubMedGoogle Scholar
  87. 87.
    Brennan PJ, Tatituri RV, Brigl M, Kim EY, Tuli A, Sanderson JP, Gadola SD, Hsu FF, Besra GS, Brenner MB (2011) Invariant natural killer T cells recognize lipid self-antigen induced by microbial danger signals. Nat Immunol 12(12):1202–1211. doi: 10.1038/ni.2143 PubMedGoogle Scholar
  88. 88.
    Fox LM, Cox DG, Lockridge JL, Wang X, Chen X, Scharf L, Trott DL, Ndonye RM, Veerapen N, Besra GS, Howell AR, Cook ME, Adams EJ, Hildebrand WH, Gumperz JE (2009) Recognition of lyso-phospholipids by human natural killer T lymphocytes. PLoS Biol 7(10):e1000228. doi: 10.1371/journal.pbio.1000228 PubMedGoogle Scholar
  89. 89.
    Joyce S, Woods AS, Yewdell JW, Bennink JR, De Silva AD, Boesteanu A, Balk SP, Cotter RJ, Brutkiewicz RR (1998) Natural ligand of mouse CD1d1: cellular glycosylphosphatidylinositol. Science 279(5356):1541–1544PubMedGoogle Scholar
  90. 90.
    Yuan W, Kang SJ, Evans JE, Cresswell P (2009) Natural lipid ligands associated with human CD1d targeted to different subcellular compartments. J Immunol 182(8):4784–4791. doi: 10.4049/jimmunol.0803981 PubMedGoogle Scholar
  91. 91.
    Haig NA, Guan Z, Li D, McMichael A, Raetz CR, Xu XN (2011) Identification of self-lipids presented by CD1c and CD1d proteins. J Biol Chem 286(43):37692–37701. doi: 10.1074/jbc.M111.267948 PubMedGoogle Scholar
  92. 92.
    van den Elzen P, Garg S, Leon L, Brigl M, Leadbetter EA, Gumperz JE, Dascher CC, Cheng TY, Sacks FM, Illarionov PA, Besra GS, Kent SC, Moody DB, Brenner MB (2005) Apolipoprotein-mediated pathways of lipid antigen presentation. Nature 437(7060):906–910. doi: 10.1038/nature04001 PubMedGoogle Scholar
  93. 93.
    Facciotti F, Ramanjaneyulu GS, Lepore M, Sansano S, Cavallari M, Kistowska M, Forss-Petter S, Ni G, Colone A, Singhal A, Berger J, Xia C, Mori L, De Libero G (2012) Peroxisome-derived lipids are self-antigens that stimulate invariant natural killer T cells in the thymus. Nat Immunol 13(5):474–480. doi: 10.1038/ni.2245 PubMedGoogle Scholar
  94. 94.
    Chen X, Wang X, Keaton JM, Reddington F, Illarionov PA, Besra GS, Gumperz JE (2007) Distinct endosomal trafficking requirements for presentation of autoantigens and exogenous lipids by human CD1d molecules. J Immunol 178(10):6181–6190PubMedGoogle Scholar
  95. 95.
    Bartke N, Hannun YA (2009) Bioactive sphingolipids: metabolism and function. J Lipid Res 50(Suppl):S91–S96. doi: 10.1194/jlr.R800080-JLR200 PubMedGoogle Scholar
  96. 96.
    Zhou D, Mattner J, Cantu C 3rd, Schrantz N, Yin N, Gao Y, Sagiv Y, Hudspeth K, Wu YP, Yamashita T, Teneberg S, Wang D, Proia RL, Levery SB, Savage PB, Teyton L, Bendelac A (2004) Lysosomal glycosphingolipid recognition by NKT cells. Science 306(5702):1786–1789. doi: 10.1126/science.1103440 PubMedGoogle Scholar
  97. 97.
    Porubsky S, Speak AO, Luckow B, Cerundolo V, Platt FM, Grone HJ (2007) Normal development and function of invariant natural killer T cells in mice with isoglobotrihexosylceramide (iGb3) deficiency. Proc Natl Acad Sci USA 104(14):5977–5982. doi: 10.1073/pnas.0611139104 PubMedGoogle Scholar
  98. 98.
    Christiansen D, Milland J, Mouhtouris E, Vaughan H, Pellicci DG, McConville MJ, Godfrey DI, Sandrin MS (2008) Humans lack iGb3 due to the absence of functional iGb3-synthase: implications for NKT cell development and transplantation. PLoS Biol 6(7):e172. doi: 10.1371/journal.pbio.0060172 PubMedGoogle Scholar
  99. 99.
    Prigozy TI, Naidenko O, Qasba P, Elewaut D, Brossay L, Khurana A, Natori T, Koezuka Y, Kulkarni A, Kronenberg M (2001) Glycolipid antigen processing for presentation by CD1d molecules. Science 291(5504):664–667. doi: 10.1126/science.291.5504.664 PubMedGoogle Scholar
  100. 100.
    Schumann J, Facciotti F, Panza L, Michieletti M, Compostella F, Collmann A, Mori L, De Libero G (2007) Differential alteration of lipid antigen presentation to NKT cells due to imbalances in lipid metabolism. Eur J Immunol 37(6):1431–1441. doi: 10.1002/eji.200737160 PubMedGoogle Scholar
  101. 101.
    Darmoise A, Teneberg S, Bouzonville L, Brady RO, Beck M, Kaufmann SH, Winau F (2010) Lysosomal alpha-galactosidase controls the generation of self-lipid antigens for natural killer T cells. Immunity 33(2):216–228. doi: 10.1016/j.immuni.2010.08.003 PubMedGoogle Scholar
  102. 102.
    Zhou D, Cantu C 3rd, Sagiv Y, Schrantz N, Kulkarni AB, Qi X, Mahuran DJ, Morales CR, Grabowski GA, Benlagha K, Savage P, Bendelac A, Teyton L (2004) Editing of CD1d-bound lipid antigens by endosomal lipid transfer proteins. Science 303(5657):523–527. doi: 10.1126/science.1092009 PubMedGoogle Scholar
  103. 103.
    Kang SJ, Cresswell P (2004) Saposins facilitate CD1d-restricted presentation of an exogenous lipid antigen to T cells. Nat Immunol 5(2):175–181. doi: 10.1038/ni1034 PubMedGoogle Scholar
  104. 104.
    Yuan W, Qi X, Tsang P, Kang SJ, Illarionov PA, Besra GS, Gumperz J, Cresswell P (2007) Saposin B is the dominant saposin that facilitates lipid binding to human CD1d molecules. Proc Natl Acad Sci USA 104(13):5551–5556. doi: 10.1073/pnas.0700617104 PubMedGoogle Scholar
  105. 105.
    Schrantz N, Sagiv Y, Liu Y, Savage PB, Bendelac A, Teyton L (2007) The Niemann-Pick type C2 protein loads isoglobotrihexosylceramide onto CD1d molecules and contributes to the thymic selection of NKT cells. J Exp Med 204(4):841–852. doi: 10.1084/jem.20061562 PubMedGoogle Scholar
  106. 106.
    Hussain MM, Shi J, Dreizen P (2003) Microsomal triglyceride transfer protein and its role in apoB-lipoprotein assembly. J Lipid Res 44(1):22–32PubMedGoogle Scholar
  107. 107.
    Dougan SK, Salas A, Rava P, Agyemang A, Kaser A, Morrison J, Khurana A, Kronenberg M, Johnson C, Exley M, Hussain MM, Blumberg RS (2005) Microsomal triglyceride transfer protein lipidation and control of CD1d on antigen-presenting cells. J Exp Med 202(4):529–539. doi: 10.1084/jem.20050183 PubMedGoogle Scholar
  108. 108.
    Brozovic S, Nagaishi T, Yoshida M, Betz S, Salas A, Chen D, Kaser A, Glickman J, Kuo T, Little A, Morrison J, Corazza N, Kim JY, Colgan SP, Young SG, Exley M, Blumberg RS (2004) CD1d function is regulated by microsomal triglyceride transfer protein. Nat Med 10(5):535–539. doi: 10.1038/nm1043 PubMedGoogle Scholar
  109. 109.
    Sagiv Y, Bai L, Wei DG, Agami R, Savage PB, Teyton L, Bendelac A (2007) A distal effect of microsomal triglyceride transfer protein deficiency on the lysosomal recycling of CD1d. J Exp Med 204(4):921–928. doi: 10.1084/jem.20061568 PubMedGoogle Scholar
  110. 110.
    Wu L, Parekh VV, Gabriel CL, Bracy DP, Marks-Shulman PA, Tamboli RA, Kim S, Mendez-Fernandez YV, Besra GS, Lomenick JP, Williams B, Wasserman DH, Van Kaer L (2012) Activation of invariant natural killer T cells by lipid excess promotes tissue inflammation, insulin resistance, and hepatic steatosis in obese mice. Proc Natl Acad Sci USA 109(19):E1143–E1152. doi: 10.1073/pnas.1200498109 PubMedGoogle Scholar
  111. 111.
    Ji Y, Sun S, Xu A, Bhargava P, Yang L, Lam KS, Gao B, Lee CH, Kersten S, Qi L (2012) Activation of natural killer T cells promotes M2 Macrophage polarization in adipose tissue and improves systemic glucose tolerance via interleukin-4 (IL-4)/STAT6 protein signaling axis in obesity. J Biol Chem 287(17):13561–13571. doi: 10.1074/jbc.M112.350066 PubMedGoogle Scholar
  112. 112.
    Lynch L, Nowak M, Varghese B, Clark J, Hogan AE, Toxavidis V, Balk SP, O’Shea D, O’Farrelly C, Exley MA (2012) Adipose tissue invariant NKT cells protect against diet-induced obesity and metabolic disorder through regulatory cytokine production. Immunity 37(3):574–587. doi: 10.1016/j.immuni.2012.06.016 PubMedGoogle Scholar
  113. 113.
    Lynch L, O’Shea D, Winter DC, Geoghegan J, Doherty DG, O’Farrelly C (2009) Invariant NKT cells and CD1d(+) cells amass in human omentum and are depleted in patients with cancer and obesity. Eur J Immunol 39(7):1893–1901. doi: 10.1002/eji.200939349 PubMedGoogle Scholar
  114. 114.
    Swift LL, Kakkad B, Boone C, Jovanovska A, Jerome WG, Mohler PJ, Ong DE (2005) Microsomal triglyceride transfer protein expression in adipocytes: a new component in fat metabolism. FEBS Lett 579(14):3183–3189. doi: 10.1016/j.febslet.2005.05.009 PubMedGoogle Scholar
  115. 115.
    Mohler PJ, Zhu MY, Blade AM, Ham AJ, Shelness GS, Swift LL (2007) Identification of a novel isoform of microsomal triglyceride transfer protein. J Biol Chem 282(37):26981–26988. doi: 10.1074/jbc.M700500200 PubMedGoogle Scholar
  116. 116.
    Shi H, Kokoeva MV, Inouye K, Tzameli I, Yin H, Flier JS (2006) TLR4 links innate immunity and fatty acid-induced insulin resistance. J Clin Investig 116(11):3015–3025. doi: 10.1172/JCI28898 PubMedGoogle Scholar
  117. 117.
    Erridge C, Samani NJ (2009) Saturated fatty acids do not directly stimulate Toll-like receptor signaling. Arterioscler Thromb Vasc Biol 29(11):1944–1949. doi: 10.1161/ATVBAHA.109.194050 PubMedGoogle Scholar
  118. 118.
    Freigang S, Landais E, Zadorozhny V, Kain L, Yoshida K, Liu Y, Deng S, Palinski W, Savage PB, Bendelac A, Teyton L (2012) Scavenger receptors target glycolipids for natural killer T cell activation. J Clin Investig 122(11):3943–3954. doi: 10.1172/JCI62267 PubMedGoogle Scholar
  119. 119.
    Huang ZH, Maeda N, Mazzone T (2011) Expression of the human apoE2 isoform in adipocytes: altered cellular processing and impaired adipocyte lipogenesis. J Lipid Res 52(9):1733–1741. doi: 10.1194/jlr.M017160 PubMedGoogle Scholar
  120. 120.
    Bedel R, Matsuda JL, Brigl M, White J, Kappler J, Marrack P, Gapin L (2012) Lower TCR repertoire diversity in Traj18-deficient mice. Nat Immunol 13(8):705–706. doi: 10.1038/ni.2347 PubMedGoogle Scholar
  121. 121.
    Kotas ME, Lee HY, Gillum MP, Annicelli C, Guigni BA, Shulman GI, Medzhitov R (2011) Impact of CD1d deficiency on metabolism. PLoS One 6(9):e25478. doi: 10.1371/journal.pone.0025478 PubMedGoogle Scholar
  122. 122.
    Ji Y, Sun S, Xia S, Yang L, Li X, Qi L (2012) Short term high fat diet challenge promotes alternative macrophage polarization in adipose tissue via natural killer T cells and interleukin-4. J Biol Chem 287(29):24378–24386. doi: 10.1074/jbc.M112.371807 PubMedGoogle Scholar
  123. 123.
    Mantell BS, Stefanovic-Racic M, Yang X, Dedousis N, Sipula IJ, O’Doherty RM (2011) Mice lacking NKT cells but with a complete complement of CD8+ T-cells are not protected against the metabolic abnormalities of diet-induced obesity. PLoS One 6(6):e19831. doi: 10.1371/journal.pone.0019831 PubMedGoogle Scholar
  124. 124.
    Ohmura K, Ishimori N, Ohmura Y, Tokuhara S, Nozawa A, Horii S, Andoh Y, Fujii S, Iwabuchi K, Onoe K, Tsutsui H (2010) Natural killer T cells are involved in adipose tissues inflammation and glucose intolerance in diet-induced obese mice. Arterioscler Thromb Vasc Biol 30(2):193–199. doi: 10.1161/ATVBAHA.109.198614 PubMedGoogle Scholar
  125. 125.
    Strodthoff D, Lundberg AM, Agardh HE, Ketelhuth DF, Paulsson-Berne G, Arner P, Hansson GK, Gerdes N (2013) Lack of invariant natural killer T cells affects lipid metabolism in adipose tissue of diet-induced obese mice. Arterioscler Thromb Vasc Biol 33(6):1189–1196. doi: 10.1161/ATVBAHA.112.301105 PubMedGoogle Scholar
  126. 126.
    Cani PD, Amar J, Iglesias MA, Poggi M, Knauf C, Bastelica D, Neyrinck AM, Fava F, Tuohy KM, Chabo C, Waget A, Delmee E, Cousin B, Sulpice T, Chamontin B, Ferrieres J, Tanti JF, Gibson GR, Casteilla L, Delzenne NM, Alessi MC, Burcelin R (2007) Metabolic endotoxemia initiates obesity and insulin resistance. Diabetes 56(7):1761–1772. doi: 10.2337/db06-1491 PubMedGoogle Scholar
  127. 127.
    Serino M, Luche E, Gres S, Baylac A, Berge M, Cenac C, Waget A, Klopp P, Iacovoni J, Klopp C, Mariette J, Bouchez O, Lluch J, Ouarne F, Monsan P, Valet P, Roques C, Amar J, Bouloumie A, Theodorou V, Burcelin R (2012) Metabolic adaptation to a high-fat diet is associated with a change in the gut microbiota. Gut 61(4):543–553. doi: 10.1136/gutjnl-2011-301012 PubMedGoogle Scholar
  128. 128.
    Nieuwenhuis EE, Matsumoto T, Lindenbergh D, Willemsen R, Kaser A, Simons-Oosterhuis Y, Brugman S, Yamaguchi K, Ishikawa H, Aiba Y, Koga Y, Samsom JN, Oshima K, Kikuchi M, Escher JC, Hattori M, Onderdonk AB, Blumberg RS (2009) Cd1d-dependent regulation of bacterial colonization in the intestine of mice. J Clin Investig 119(5):1241–1250. doi: 10.1172/JCI36509 PubMedGoogle Scholar
  129. 129.
    Wei B, Wingender G, Fujiwara D, Chen DY, McPherson M, Brewer S, Borneman J, Kronenberg M, Braun J (2010) Commensal microbiota and CD8 + T cells shape the formation of invariant NKT cells. J Immunol 184(3):1218–1226. doi: 10.4049/jimmunol.0902620 PubMedGoogle Scholar
  130. 130.
    Wingender G, Stepniak D, Krebs P, Lin L, McBride S, Wei B, Braun J, Mazmanian SK, Kronenberg M (2012) Intestinal microbes affect phenotypes and functions of invariant natural killer T cells in mice. Gastroenterology 143(2):418–428. doi: 10.1053/j.gastro.2012.04.017 PubMedGoogle Scholar
  131. 131.
    Macotela Y, Boucher J, Tran TT, Kahn CR (2009) Sex and depot differences in adipocyte insulin sensitivity and glucose metabolism. Diabetes 58(4):803–812. doi: 10.2337/db08-1054 PubMedGoogle Scholar
  132. 132.
    Mathis D (2013) Immunological goings-on in visceral adipose tissue. Cell Metab 17(6):851–859. doi: 10.1016/j.cmet.2013.05.008 PubMedGoogle Scholar
  133. 133.
    Ferrante AW Jr (2007) Obesity-induced inflammation: a metabolic dialogue in the language of inflammation. J Intern Med 262(4):408–414. doi: 10.1111/j.1365-2796.2007.01852.x PubMedGoogle Scholar
  134. 134.
    Odegaard JI, Chawla A (2011) Alternative macrophage activation and metabolism. Annu Rev Pathol 6:275–297. doi: 10.1146/annurev-pathol-011110-130138 PubMedGoogle Scholar
  135. 135.
    Cinti S, Mitchell G, Barbatelli G, Murano I, Ceresi E, Faloia E, Wang S, Fortier M, Greenberg AS, Obin MS (2005) Adipocyte death defines macrophage localization and function in adipose tissue of obese mice and humans. J Lipid Res 46(11):2347–2355. doi: 10.1194/jlr.M500294-JLR200 PubMedGoogle Scholar
  136. 136.
    Strissel KJ, Stancheva Z, Miyoshi H, Perfield JW 2nd, DeFuria J, Jick Z, Greenberg AS, Obin MS (2007) Adipocyte death, adipose tissue remodeling, and obesity complications. Diabetes 56(12):2910–2918. doi: 10.2337/db07-0767 PubMedGoogle Scholar
  137. 137.
    Gordon S, Martinez FO (2010) Alternative activation of macrophages: mechanism and functions. Immunity 32(5):593–604. doi: 10.1016/j.immuni.2010.05.007 PubMedGoogle Scholar
  138. 138.
    Odegaard JI, Ricardo-Gonzalez RR, Goforth MH, Morel CR, Subramanian V, Mukundan L, Red Eagle A, Vats D, Brombacher F, Ferrante AW, Chawla A (2007) Macrophage-specific PPARgamma controls alternative activation and improves insulin resistance. Nature 447(7148):1116–1120. doi: 10.1038/nature05894 PubMedGoogle Scholar
  139. 139.
    Wu D, Molofsky AB, Liang HE, Ricardo-Gonzalez RR, Jouihan HA, Bando JK, Chawla A, Locksley RM (2011) Eosinophils sustain adipose alternatively activated macrophages associated with glucose homeostasis. Science 332(6026):243–247. doi: 10.1126/science.1201475 PubMedGoogle Scholar
  140. 140.
    Schmieg J, Yang G, Franck RW, Tsuji M (2003) Superior protection against malaria and melanoma metastases by a C-glycoside analogue of the natural killer T cell ligand alpha-Galactosylceramide. J Exp Med 198(11):1631–1641. doi: 10.1084/jem.20031192 PubMedGoogle Scholar
  141. 141.
    Bai L, Constantinides MG, Thomas SY, Reboulet R, Meng F, Koentgen F, Teyton L, Savage PB, Bendelac A (2012) Distinct APCs explain the cytokine bias of alpha-galactosylceramide variants in vivo. J Immunol 188(7):3053–3061. doi: 10.4049/jimmunol.1102414 PubMedGoogle Scholar
  142. 142.
    Fujii S, Liu K, Smith C, Bonito AJ, Steinman RM (2004) The linkage of innate to adaptive immunity via maturing dendritic cells in vivo requires CD40 ligation in addition to antigen presentation and CD80/86 costimulation. J Exp Med 199(12):1607–1618. doi: 10.1084/jem.20040317 PubMedGoogle Scholar
  143. 143.
    Bezbradica JS, Stanic AK, Matsuki N, Bour-Jordan H, Bluestone JA, Thomas JW, Unutmaz D, Van Kaer L, Joyce S (2005) Distinct roles of dendritic cells and B cells in Va14Ja18 natural T cell activation in vivo. J Immunol 174(8):4696–4705PubMedGoogle Scholar
  144. 144.
    Caligiuri MA (2008) Human natural killer cells. Blood 112(3):461–469. doi: 10.1182/blood-2007-09-077438 PubMedGoogle Scholar
  145. 145.
    Bellora F, Castriconi R, Dondero A, Reggiardo G, Moretta L, Mantovani A, Moretta A, Bottino C (2010) The interaction of human natural killer cells with either unpolarized or polarized macrophages results in different functional outcomes. Proc Natl Acad Sci USA 107(50):21659–21664. doi: 10.1073/pnas.1007654108 PubMedGoogle Scholar
  146. 146.
    Lapaque N, Walzer T, Meresse S, Vivier E, Trowsdale J (2009) Interactions between human NK cells and macrophages in response to Salmonella infection. J Immunol 182(7):4339–4348. doi: 10.4049/jimmunol.0803329 PubMedGoogle Scholar
  147. 147.
    Dalbeth N, Gundle R, Davies RJ, Lee YC, McMichael AJ, Callan MF (2004) CD56bright NK cells are enriched at inflammatory sites and can engage with monocytes in a reciprocal program of activation. J Immunol 173(10):6418–6426PubMedGoogle Scholar
  148. 148.
    Schmieg J, Yang G, Franck RW, Van Rooijen N, Tsuji M (2005) Glycolipid presentation to natural killer T cells differs in an organ-dependent fashion. Proc Natl Acad Sci USA 102(4):1127–1132. doi: 10.1073/pnas.0408288102 PubMedGoogle Scholar
  149. 149.
    Winau F, Hegasy G, Weiskirchen R, Weber S, Cassan C, Sieling PA, Modlin RL, Liblau RS, Gressner AM, Kaufmann SH (2007) Ito cells are liver-resident antigen-presenting cells for activating T cell responses. Immunity 26(1):117–129. doi: 10.1016/j.immuni.2006.11.011 PubMedGoogle Scholar
  150. 150.
    Barral P, Polzella P, Bruckbauer A, van Rooijen N, Besra GS, Cerundolo V, Batista FD (2010) CD169(+) macrophages present lipid antigens to mediate early activation of iNKT cells in lymph nodes. Nat Immunol 11(4):303–312. doi: 10.1038/ni.1853 PubMedGoogle Scholar
  151. 151.
    Campbell DJ, Koch MA (2011) Phenotypical and functional specialization of FOXP3+ regulatory T cells. Nat Rev Immunol 11(2):119–130. doi: 10.1038/nri2916 PubMedGoogle Scholar
  152. 152.
    Sakaguchi S (2004) Naturally arising CD4 + regulatory t cells for immunologic self-tolerance and negative control of immune responses. Annu Rev Immunol 22:531–562. doi: 10.1146/annurev.immunol.21.120601.141122 PubMedGoogle Scholar
  153. 153.
    Hori S, Nomura T, Sakaguchi S (2003) Control of regulatory T cell development by the transcription factor Foxp3. Science 299(5609):1057–1061. doi: 10.1126/science.1079490 PubMedGoogle Scholar
  154. 154.
    Feuerer M, Hill JA, Mathis D, Benoist C (2009) Foxp3+ regulatory T cells: differentiation, specification, subphenotypes. Nat Immunol 10(7):689–695. doi: 10.1038/ni.1760 PubMedGoogle Scholar
  155. 155.
    Cipolletta D, Kolodin D, Benoist C, Mathis D (2011) Tissular T(regs): a unique population of adipose-tissue-resident Foxp3+CD4+ T cells that impacts organismal metabolism. Semin Immunol 23(6):431–437. doi: 10.1016/j.smim.2011.06.002 PubMedGoogle Scholar
  156. 156.
    Feuerer M, Herrero L, Cipolletta D, Naaz A, Wong J, Nayer A, Lee J, Goldfine AB, Benoist C, Shoelson S, Mathis D (2009) Lean, but not obese, fat is enriched for a unique population of regulatory T cells that affect metabolic parameters. Nat Med 15(8):930–939. doi: 10.1038/nm.2002 PubMedGoogle Scholar
  157. 157.
    Jiang S, Game DS, Davies D, Lombardi G, Lechler RI (2005) Activated CD1d-restricted natural killer T cells secrete IL-2: innate help for CD4+CD25+ regulatory T cells? Eur J Immunol 35(4):1193–1200. doi: 10.1002/eji.200425899 PubMedGoogle Scholar
  158. 158.
    Bluestone JA, Tang Q (2004) Therapeutic vaccination using CD4+CD25+ antigen-specific regulatory T cells. Proc Natl Acad Sci USA 101(Suppl 2):14622–14626. doi: 10.1073/pnas.0405234101 PubMedGoogle Scholar
  159. 159.
    Azuma T, Takahashi T, Kunisato A, Kitamura T, Hirai H (2003) Human CD4+CD25+ regulatory T cells suppress NKT cell functions. Cancer Res 63(15):4516–4520PubMedGoogle Scholar
  160. 160.
    Tiemessen MM, Jagger AL, Evans HG, van Herwijnen MJ, John S, Taams LS (2007) CD4+CD25+Foxp3+ regulatory T cells induce alternative activation of human monocytes/macrophages. Proc Natl Acad Sci USA 104(49):19446–19451. doi: 10.1073/pnas.0706832104 PubMedGoogle Scholar

Copyright information

© Springer Basel 2013

Authors and Affiliations

  1. 1.Section Metabolic Diseases, Department of Molecular Cancer ResearchUniversity Medical Center UtrechtUtrechtThe Netherlands
  2. 2.Department of Pediatric Immunology, Wilhelmina Children’s HospitalUniversity Medical Center UtrechtUtrechtThe Netherlands

Personalised recommendations