Review Article | Published:

Tissue-specific functions of invariant natural killer T cells

Nature Reviews Immunologyvolume 18pages559574 (2018) | Download Citation


Invariant natural killer T cells (iNKT cells) are an innate-like T cell subset that expresses an invariant T cell receptor (TCR) α-chain and recognizes lipids presented on CD1d. They secrete diverse cytokines and can influence many types of immune responses. Despite having highly similar TCR specificities, iNKT cells differentiate in the thymus into distinct subsets that are analogous to T helper 1 (TH1), TH2 and TH17 cell subsets. Additional iNKT cell subsets that may require peripheral activation have also been described, including one that produces IL-10. In general, iNKT cells are non-circulating, tissue-resident lymphocytes, but the prevalence of different iNKT cell subsets differs markedly between tissues. Here, we summarize the functions of iNKT cells in four tissues in which they are prevalent, namely, the liver, the lungs, adipose tissue and the intestine. Importantly, we explain how local iNKT cell responses at each site contribute to tissue homeostasis and protection from infection but can also contribute to tissue inflammation and damage.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Additional information

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.


  1. 1.

    Lantz, O. & Bendelac, A. An invariant T cell receptor α chain is used by a unique subset of major histocompatibility complex class I-specific CD4+ and CD48 T cells in mice and humans. J. Exp. Med. 180, 1097–1106 (1994).

  2. 2.

    Dellabona, P., Padovan, E., Casorati, G., Brockhaus, M. & Lanzavecchia, A. An invariant Vα 4-JαQ/Vβ11 T cell receptor is expressed in all individuals by clonally expanded CD48 T cells. J. Exp. Med. 180, 1171–1176 (1994).

  3. 3.

    Bendelac, A. et al. CD1 recognition by mouse NK1+ T lymphocytes. Science 268, 863–865 (1995).

  4. 4.

    Kawano, T. et al. CD1d-restricted and TCR-mediated activation of vα14 NKT cells by glycosylceramides. Science 278, 1626–1629 (1997).

  5. 5.

    Burdin, N. et al. Selective ability of mouse CD1 to present glycolipids: α-galactosylceramide specifically stimulates Vα14+ NK T lymphocytes. J. Immunol. 161, 3271–3281 (1998).

  6. 6.

    Brigl, M. & Brenner, M. B. How invariant natural killer T cells respond to infection by recognizing microbial or endogenous lipid antigens. Semin. Immunol. 22, 79–86 (2010).

  7. 7.

    Kinjo, Y. et al. Natural killer T cells recognize diacylglycerol antigens from pathogenic bacteria. Nat. Immunol. 7, 978–986 (2006).

  8. 8.

    Kinjo, Y. et al. Invariant natural killer T cells recognize glycolipids from pathogenic Gram-positive bacteria. Nat. Immunol. 12, 966–974 (2011). References 7 and 8 identify specific lipid antigens from pathogenic bacteria that activate iNKT cells in a CD1d-dependent manner.

  9. 9.

    De Libero, G. & Mori, L. Recognition of lipid antigens by T cells. Nat. Rev. Immunol. 5, 485–496 (2005).

  10. 10.

    Brennan, P. J. et al. Invariant natural killer T cells recognize lipid self antigen induced by microbial danger signals. Nat. Immunol. 12, 1202–1211 (2011).

  11. 11.

    Saroha, A. et al. Critical role for very-long chain sphingolipids in invariant natural killer T cell development and homeostasis. Front. Immunol. 8, 1386 (2017).

  12. 12.

    Kumar, A. et al. Natural killer T cells: an ecological evolutionary developmental biology perspective. Front. Immunol. 8, 1858 (2017).

  13. 13.

    Brossay, L. et al. CD1d-mediated recognition of an alpha-galactosylceramide by natural killer T cells is highly conserved through mammalian evolution. J. Exp. Med. 188, 1521–1528 (1998).

  14. 14.

    Gapin, L. Development of invariant natural killer T cells. Curr. Opin. Immunol. 39, 68–74 (2016).

  15. 15.

    Bollino, D. & Webb, T. J. Chimeric antigen receptor-engineered natural killer and natural killer T cells for cancer immunotherapy. Transl Res. 187, 32–43 (2017).

  16. 16.

    Heczey, A. et al. Invariant NKT cells with chimeric antigen receptor provide a novel platform for safe and effective cancer immunotherapy. Blood 124, 2824–2833 (2014). This study describes the novel use of iNKT cells as a platform for chimeric antigen receptor (CAR) T cell cancer therapy.

  17. 17.

    Wolf, B. J., Choi, J. E. & Exley, M. A. Novel approaches to exploiting invariant NKT cells in cancer immunotherapy. Front. Immunol. 9, 384 (2018).

  18. 18.

    Harrer, D. C., Dörrie, J. & Schaft, N. Chimeric antigen receptors in different cell types: new vehicles join the race. Hum. Gene Ther. 29, 547–558 (2018).

  19. 19.

    Bennstein, S. B. Unraveling natural killer T-cells development. Front. Immunol. 8, 1950 (2017).

  20. 20.

    Georgiev, H., Ravens, I., Benarafa, C., Förster, R. & Bernhardt, G. Distinct gene expression patterns correlate with developmental and functional traits of iNKT subsets. Nat. Commun. 7, 13116 (2016).

  21. 21.

    Lee, Y. J. et al. Lineage-specific effector signatures of invariant NKT cells are shared amongst γδ T, innate lymphoid, and Th cells. J. Immunol. 197, 1460–1470 (2016).

  22. 22.

    Lee, Y. J., Holzapfel, K. L., Zhu, J., Jameson, S. C. & Hogquist, K. A. Steady-state production of IL-4 modulates immunity in mouse strains and is determined by lineage diversity of iNKT cells. Nat. Immunol. 14, 1146 (2013).

  23. 23.

    Verykokakis, M. & Kee, B. L. Transcriptional and epigenetic regulation of innate-like T lymphocyte development. Curr. Opin. Immunol. 51, 39–45 (2018).

  24. 24.

    Engel, I. et al. Innate-like functions of natural killer T cell subsets result from highly divergent gene programs. Nat. Immunol. 17, 728–739 (2016). References 20, 21 and 24 show that the gene programmes of thymic iNKT cell subsets are strikingly different.

  25. 25.

    Godfrey, D. I., Stankovic, S. & Baxter, A. G. Raising the NKT cell family. Nat. Immunol. 11, 197–206 (2010).

  26. 26.

    Gumperz, J. E., Miyake, S., Yamamura, T. & Brenner, M. B. Functionally distinct subsets of CD1d-restricted natural killer T cells revealed by CD1d tetramer staining. J. Exp. Med. 195, 625–636 (2002).

  27. 27.

    Lee, P. T., Benlagha, K., Teyton, L. & Bendelac, A. Distinct functional lineages of human Vα24 natural killer T cells. J. Exp. Med. 195, 637–641 (2002).

  28. 28.

    Godfrey, D. I. & Berzins, S. P. Control points in NKT-cell development. Nat. Rev. Immunol. 7, 505 (2007).

  29. 29.

    Moreira-Teixeira, L. et al. Proinflammatory environment dictates the IL-17-producing capacity of human invariant NKT cells. J. Immunol. 186, 5758–5765 (2011).

  30. 30.

    Berzins, S. P., McNab, F. W., Jones, C. M., Smyth, M. J. & Godfrey, D. I. Long-term retention of mature NK1.1+ NKT cells in the thymus. J. Immunol. 176, 4059–4065 (2006).

  31. 31.

    Weinreich, M. A., Odumade, O. A., Jameson, S. C. & Hogquist, K. A. T cells expressing the transcription factor PLZF regulate the development of memory-like CD8+ T cells. Nat. Immunol. 11, 709–716 (2010).

  32. 32.

    Eberl, G., Brawand, P. & MacDonald, H. R. Selective bystander proliferation of memory CD4+ and CD8+ T cells upon NK T or T cell activation. J. Immunol. 165, 4305–4311 (2000).

  33. 33.

    White, A. J., Lucas, B., Jenkinson, W. E. & Anderson, G. Invariant NKT cells and control of the thymus medulla. J. Immunol. 200, 3333–3339 (2018).

  34. 34.

    Lynch, L. et al. Regulatory iNKT cells lack expression of the transcription factor PLZF and control the homeostasis of Treg cells and macrophages in adipose tissue. Nat. Immunol. 16, 85–95 (2015). This study identifies a regulatory iNKT cell subset in the adipose tissue, which lacks expression of the hallmark transcription factor PLZF and produces IL-10.

  35. 35.

    Thomas, S. Y. et al. PLZF induces an intravascular surveillance program mediated by long-lived LFA-1-ICAM-1 interactions. J. Exp. Med. 208, 1179–1188 (2011). This is the first demonstration that iNKT cells are tissue resident.

  36. 36.

    Matsuda, J. L. et al. Homeostasis of Vα14i NKT cells. Nat. Immunol. 3, 966–974 (2002).

  37. 37.

    McNab, F. W. et al. The influence of CD1d in postselection NKT cell maturation and homeostasis. J. Immunol. 175, 3762–3768 (2005).

  38. 38.

    Wei, D. G. et al. Expansion and long-range differentiation of the NKT cell lineage in mice expressing CD1d exclusively on cortical thymocytes. J. Exp. Med. 202, 239–248 (2005).

  39. 39.

    Leignadier, J., Hardy, M.-P., Cloutier, M., Rooney, J. & Labrecque, N. Memory T-lymphocyte survival does not require T cell receptor expression. Proc. Natl Acad. Sci. USA 105, 20440–20445 (2008).

  40. 40.

    Boyman, O., Krieg, C., Homann, D. & Sprent, J. Homeostatic maintenance of T cells and natural killer cells. Cell. Mol. Life Sci. 69, 1597–1608 (2012).

  41. 41.

    Zeissig, S. et al. CD1d-restricted pathways in hepatocytes control local natural killer T cell homeostasis and hepatic inflammation. Proc. Natl Acad. Sci. USA 114, 10449–10454 (2017).

  42. 42.

    Sáez de Guinoa, J. et al. CD1d-mediated lipid presentation by CD11c+ cells regulates intestinal homeostasis. EMBO J. 37, e97537 (2018). This study shows that CD1d and iNKT cells control intestinal bacteria composition and intestinal homeostasis.

  43. 43.

    Ranson, T. et al. IL-15 availability conditions homeostasis of peripheral natural killer T cells. Proc. Natl Acad. Sci. USA 100, 2663–2668 (2003).

  44. 44.

    Webster, K. E. et al. IL-17-producing NKT cells depend exclusively on IL-7 for homeostasis and survival. Mucosal Immunol. 7, 1058–1067 (2014).

  45. 45.

    Lee, Y. J. et al. Tissue-specific distribution of iNKT cells impacts their cytokine response. Immunity 43, 566–578 (2015). This study demonstrates that iNKT cell subsets localize to different tissues and that this affects their ability to respond to antigens.

  46. 46.

    Kastenmüller, W., Torabi-Parizi, P., Subramanian, N., Lämmermann, T. & Germain, R. N. A spatially-organized multicellular innate immune response in lymph nodes limits systemic pathogen spread. Cell 150, 1235–1248 (2012).

  47. 47.

    Gaya, M. et al. Initiation of antiviral B cell immunity relies on innate signals from spatially positioned NKT cells. Cell 172, 517–533 (2018).

  48. 48.

    Barral, P. et al. CD169+ macrophages present lipid antigens to mediate early activation of iNKT cells in lymph nodes. Nat. Immunol. 11, 303–312 (2010).

  49. 49.

    Pellicci, D. G. et al. A natural killer T (NKT) cell developmental pathway involving a thymus-dependent NK1.1CD4+ CD1d-dependent precursor stage. J. Exp. Med. 195, 835–844 (2002).

  50. 50.

    Milpied, P. et al. IL-17-producing invariant NKT cells in lymphoid organs are recent thymic emigrants identified by neuropilin-1 expression. Blood 118, 2993–3002 (2011).

  51. 51.

    Baev, D. V. et al. Distinct homeostatic requirements of CD4+ and CD4 subsets of Vα24-invariant natural killer T cells in humans. Blood 104, 4150–4156 (2004).

  52. 52.

    Berzins, S. P., Cochrane, A. D. & Pellicci, D. G. Limited correlation between human thymus and blood NKT cell content revealed by an ontogeny study of paired tissue samples. Eur. J. Immunol. 35, 1399–1407 (2005).

  53. 53.

    Chang, P.-P. et al. Identification of Bcl-6-dependent follicular helper NKT cells that provide cognate help for B cell responses. Nat. Immunol. 13, 35–43 (2011).

  54. 54.

    King, I. L. et al. Invariant natural killer T cells direct B cell responses to cognate lipid antigen in an IL-21-dependent manner. Nat. Immunol. 13, 44–50 (2011).

  55. 55.

    Wingender, G., Sag, D. & Kronenberg, M. NKT10 cells: a novel iNKT cell subset. Oncotarget 6, 26552–26553 (2015).

  56. 56.

    Sag, D., Krause, P., Hedrick, C. C., Kronenberg, M. & Wingender, G. IL-10-producing NKT10 cells are a distinct regulatory invariant NKT cell subset. J. Clin. Invest. 124, 3725–3740 (2014).

  57. 57.

    Vieth, J. A. et al. TCRα-TCRβ pairing controls recognition of CD1d and directs the development of adipose NKT cells. Nat. Immunol. 18, 36–44 (2017).

  58. 58.

    Motomura, Y. et al. The transcription factor E4BP4 regulates the production of IL-10 and IL-13 in CD4+ T cells. Nat. Immunol. 12, 450–459 (2011).

  59. 59.

    Kim, H. S. & Chung, D. H. IL-9-producing invariant NKT cells protect against DSS-induced colitis in an IL-4-dependent manner. Mucosal Immunol. 6, 347–357 (2013).

  60. 60.

    Monteiro, M. et al. IL-9 expression by invariant NKT cells is not imprinted during thymic development. J. Immunol. 195, 3463–3471 (2015).

  61. 61.

    Goto, M. et al. Murine NKT cells produce Th17 cytokine interleukin-22. Cell. Immunol. 254, 81–84 (2009).

  62. 62.

    Doisne, J. M. et al. Cutting edge: crucial role of IL-1 and IL-23 in the innate IL-17 response of peripheral lymph node NK1.1 invariant NKT cells to bacteria. J. Immunol. 186, 662–666 (2011).

  63. 63.

    Paget, C. et al. Interleukin-22 is produced by invariant natural killer T lymphocytes during influenza A virus infection: potential role in protection against lung epithelial damages. J. Biol. Chem. 287, 8816–8829 (2012).

  64. 64.

    Monteiro, M. et al. Identification of regulatory Foxp3+ invariant NKT cells induced by TGF. J. Immunol. 185, 2157–2163 (2010).

  65. 65.

    Brigl, M. et al. Innate and cytokine-driven signals, rather than microbial antigens, dominate in natural killer T cell activation during microbial infection. J. Exp. Med. 208, 1163–1177 (2011).

  66. 66.

    Velazquez, P. et al. Cutting edge: activation by innate cytokines or microbial antigens can cause arrest of natural killer T cell patrolling of liver sinusoids. J. Immunol. 180, 2024–2028 (2008).

  67. 67.

    Smithgall, M. D. et al. IL-33 amplifies both Th1- and Th2-type responses through its activity on human basophils, allergen-reactive Th2 cells, iNKT and NK Cells. Int. Immunol. 20, 1019–1030 (2008).

  68. 68.

    Wang, X. et al. Human invariant natural killer T cells acquire transient innate responsiveness via histone H4 acetylation induced by weak TCR stimulation. J. Exp. Med. 209, 987–1000 (2012).

  69. 69.

    Godfrey, D. I. & Kronenberg, M. Going both ways: immune regulation via CD1d-dependent NKT cells. J. Clin. Invest. 114, 1379–1388 (2004).

  70. 70.

    Ohteki, T. & MacDonald, H. R. Major histocompatibility complex class I related molecules control the development of CD4+8 and CD48 subsets of natural killer 1.1+ T cell receptor-α/β+ cells in the liver of mice. J. Exp. Med. 180, 699–704 (1994).

  71. 71.

    Matsuda, J. L. et al. Tracking the response of natural killer T cells to a glycolipid antigen using CD1d tetramers. J. Exp. Med. 192, 741–754 (2000).

  72. 72.

    Santodomingo-Garzon, T. & Swain, M. G. Role of NKT cells in autoimmune liver disease. Autoimmun. Rev. 10, 793–800 (2011).

  73. 73.

    Syn, W.-K. et al. Accumulation of natural killer T cells in progressive nonalcoholic fatty liver disease. Hepatology 51, 1998–2007 (2010).

  74. 74.

    Liang, B. et al. Role of hepatocyte-derived IL-7 in maintenance of intrahepatic NKT cells and T cells and development of B cells in fetal liver. J. Immunol. 189, 4444–4450 (2012).

  75. 75.

    Emoto, M., Mittrücker, H.-W., Schmits, R., Mak, T. W. & Kaufmann, S. H. E. Critical role of leukocyte function-associated antigen-1 in liver accumulation of CD4+NKT Cells. J. Immunol. 162, 5094–5098 (1999).

  76. 76.

    Geissmann, F. et al. Intravascular immune surveillance by CXCR6+ NKT cells patrolling liver sinusoids. PLOS Biol. 3, e113 (2005).

  77. 77.

    Ohteki, T., Maki, C., Koyasu, S., Mak, T. W. & Ohashi, P. S. Cutting edge: LFA-1 is required for liver NK1.1+TCRαβ+ cell development: evidence that liver NK1.1+TCRαβ+ cells originate from multiple pathways. J. Immunol. 162, 3753–3756 (1999).

  78. 78.

    Germanov, E. et al. Critical role for the chemokine receptor CXCR6 in homeostasis and activation of CD1d-restricted NKT cells. J. Immunol. 181, 81–91 (2008).

  79. 79.

    Monticelli, L. A. et al. Transcriptional regulator Id2 controls survival of hepatic NKT cells. Proc. Natl Acad. Sci. USA 106, 19461–19466 (2009).

  80. 80.

    Mackay, L. K. et al. Hobit and Blimp1 instruct a universal transcriptional program of tissue residency in lymphocytes. Science 352, 459–463 (2016).

  81. 81.

    Lee, W.-Y. et al. An intravascular immune response to Borrelia burgdorferi involves Kupffer cells and iNKT cells. Nat. Immunol. 11, 295–302 (2010). References 76 and 81 use intravital microscopy to characterize the movement of iNKT cells in the liver sinusoids after αGalCer injection and B. burgdorferi infection.

  82. 82.

    Ichikawa, S., Mucida, D., Tyznik, A. J., Kronenberg, M. & Cheroutre, H. Hepatic stellate cells function as regulatory bystanders. J. Immunol. 186, 5549–5555 (2011).

  83. 83.

    Mattner, J. et al. Exogenous and endogenous glycolipid antigens activate NKT cells during microbial infections. Nature 434, 525–529 (2005).

  84. 84.

    Tupin, E. et al. NKT cells prevent chronic joint inflammation after infection with Borrelia burgdorferi. Proc. Natl Acad. Sci. USA 105, 19863–19868 (2008).

  85. 85.

    Olson, C. M. et al. Local production of IFN-γ by invariant NKT cells modulates acute Lyme carditis. J. Immunol. 182, 3728–3734 (2009).

  86. 86.

    Kumar, H., Belperron, A., Barthold, S. W. & Bockenstedt, L. K. Cutting edge: CD1d deficiency impairs murine host defense against the spirochete Borrelia burgdorferi. J. Immunol. 165, 4797–4801 (2000).

  87. 87.

    Miyaki, E. et al. Interferon α treatment stimulates interferon γ expression in type I NKT cells and enhances their antiviral effect against hepatitis C virus. PLOS One 12, e0172412 (2017).

  88. 88.

    Deignan, T. et al. Decrease in hepatic CD56+ T cells and Vα24+ natural killer T cells in chronic hepatitis C viral infection. J. Hepatol. 37, 101–108 (2002).

  89. 89.

    Lucas, M. et al. Frequency and phenotype of circulating Vα24/Vβ11 double-positive natural killer T cells during hepatitis C virus infection. J. Virol. 77, 2251–2257 (2003).

  90. 90.

    van der Vliet, H. J. J. et al. Circulating Vα24+Vβ11+ NKT cell numbers and dendritic cell CD1d expression in hepatitis C virus infected patients. Clin. Immunol. 114, 183–189 (2005).

  91. 91.

    Jiang, X. et al. Restored circulating invariant NKT cells are associated with viral control in patients with chronic hepatitis B. PLOS One 6, e28871 (2011).

  92. 92.

    Zeissig, S. et al. Hepatitis B virus-induced lipid alterations contribute to natural killer T cell-dependent protective immunity. Nat. Med. 18, 1060–1068 (2012).

  93. 93.

    Takeda, K. et al. Critical contribution of liver natural killer T cells to a murine model of hepatitis. Proc. Natl Acad. Sci. USA 97, 5498–5503 (2000).

  94. 94.

    Ajuebor, M. N. et al. Lack of chemokine receptor CCR5 promotes murine fulminant liver failure by preventing the apoptosis of activated CD1d-restricted NKT cells. J. Immunol. 174, 8027–8037 (2005).

  95. 95.

    Syn, W.-K. et al. NKT-associated hedgehog and osteopontin drive fibrogenesis in non-alcoholic fatty liver disease. Gut 61, 1323–1329 (2012).

  96. 96.

    Wolf, M. J. et al. Metabolic activation of intrahepatic CD8+ T cells and NKT cells causes nonalcoholic steatohepatitis and liver cancer via cross-talk with hepatocytes. Cancer Cell 26, 549–564 (2014).

  97. 97.

    Bhattacharjee, J. et al. Hepatic natural killer T cell and CD8+ T cell signatures in mice with nonalcoholic steatohepatitis. Hepatol. Commun. 1, 299–310 (2017).

  98. 98.

    Tajiri, K., Shimizu, Y., Tsuneyama, K. & Sugiyama, T. Role of liver-infiltrating CD3+CD56+ natural killer T cells in the pathogenesis of nonalcoholic fatty liver disease. Eur. J. Gastroenterol. Hepatol. 21, 673–680 (2009).

  99. 99.

    Chiaramonte, M. G., Donaldson, D. D., Cheever, A. W. & Wynn, T. A. An IL-13 inhibitor blocks the development of hepatic fibrosis during a T-helper type 2-dominated inflammatory response. J. Clin. Invest. 104, 777–785 (1999).

  100. 100.

    Fichtner-Feigl, S., Strober, W., Kawakami, K., Puri, R. K. & Kitani, A. IL-13 signaling through the IL-13α2 receptor is involved in induction of TGF-β1 production and fibrosis. Nat. Med. 12, 99–106 (2006).

  101. 101.

    Jiang, W., Sun, R., Zhou, R., Wei, H. & Tian, Z. TLR-9 activation aggravates concanavalin a-induced hepatitis via promoting accumulation and activation of liver CD4+ NKT Cells. J. Immunol. 182, 3768–3774 (2009).

  102. 102.

    Dong, Z., Zhang, J., Sun, R., Wei, H. & Tian, Z. Impairment of liver regeneration correlates with activated hepatic NKT cells in HBV transgenic mice. Hepatology 45, 1400–1412 (2007).

  103. 103.

    Ito, H. Role of Vα 14 NKT cells in the development of impaired liver regeneration in vivo. Hepatology 38, 1116–1124 (2003).

  104. 104.

    Jin, Z. et al. Accelerated liver fibrosis in hepatitis B virus transgenic mice: involvement of natural killer T cells. Hepatology 53, 219–229 (2011).

  105. 105.

    Hines, I. N., Kremer, M., Moore, S. M. & Wheeler, M. D. Impaired T cell-mediated hepatitis in peroxisome proliferator activated receptor alpha (PPARα)-deficient mice. Biol. Res. 51, 5 (2018).

  106. 106.

    Schrumpf, E. et al. The role of natural killer T cells in a mouse model with spontaneous bile duct inflammation. Physiol. Rep. 5, e13117 (2017).

  107. 107.

    Chuang, Y.-H. et al. Natural killer T cells exacerbate liver injury in a transforming growth factor β receptor II dominant-negative mouse model of primary biliary cirrhosis. Hepatology 47, 571–580 (2008).

  108. 108.

    Kita, H. et al. Quantitation and phenotypic analysis of natural killer T cells in primary biliary cirrhosis using a human CD1d tetramer. Gastroenterology 123, 1031–1043 (2002).

  109. 109.

    Lappas, C. M., Day, Y.-J., Marshall, M. A., Engelhard, V. H. & Linden, J. Adenosine A2A receptor activation reduces hepatic ischemia reperfusion injury by inhibiting CD1d-dependent NKT cell activation. J. Exp. Med. 203, 2639–2648 (2006). This study provides a demonstration of activation of liver iNKT cells that is induced by sterile inflammation contributing to tissue injury.

  110. 110.

    Milosavljevic, N. et al. Mesenchymal stem cells attenuate acute liver injury by altering ratio between interleukin 17 producing and regulatory natural killer T cells. Liver Transpl. 23, 1040–1050 (2017).

  111. 111.

    Wu, D. et al. Activated NKT cells facilitated functional switch of myeloid-derived suppressor cells at inflammation sites in fulminant hepatitis mice. Immunobiology 222, 440–449 (2017).

  112. 112.

    Yin, S. et al. Activation of invariant natural killer T cells impedes liver regeneration by way of both IFN-γ- and IL-4-dependent mechanisms. Hepatology 60, 1356–1366 (2014).

  113. 113.

    Ben Ya’acov,A., Meir, H., Zolotaryova, L., Ilan, Y. & Shteyer, E. Impaired liver regeneration is associated with reduced cyclin B1 in natural killer T cell-deficient mice. BMC Gastroenterol. 17, 44 (2017).

  114. 114.

    Liew, P. X., Lee, W.-Y. & Kubes, P. iNKT cells orchestrate a switch from inflammation to resolution of sterile liver injury. Immunity 47, 752–765.e5 (2017). This study shows how iNKT cells can aid in wound healing in the liver at later times following sterile injury.

  115. 115.

    Scanlon, S. T. et al. Airborne lipid antigens mobilize resident intravascular NKT cells to induce allergic airway inflammation. J. Exp. Med. 208, 2113–2124 (2011). This study illustrates the extravasation of lung iNKT cells from the vasculature to the interstitial tissue following airborne lipid antigen exposure, which triggers long-term susceptibility to allergic airway inflammation.

  116. 116.

    Hill, T. M. et al. Border patrol gone awry: lung NKT cell activation by Francisella tularensis exacerbates tularemia-like disease. PLOS Pathog. 11, e1004975 (2015).

  117. 117.

    Thanabalasuriar, A., Neupane, A. S., Wang, J., Krummel, M. F. & Kubes, P. iNKT cell emigration out of the lung vasculature requires neutrophils and monocyte-derived dendritic cells in inflammation. Cell Rep. 16, 3260–3272 (2016).

  118. 118.

    Kawakami, K. et al. Critical role of Vα14+ natural killer T cells in the innate phase of host protection against Streptococcus pneumoniae infection. Eur. J. Immunol. 33, 3322–3330 (2003).

  119. 119.

    Cha, H. et al. Differential pulmonic NK and NKT cell responses in Schistosoma japonicum-infected mice. Parasitol. Res. 116, 559–567 (2017).

  120. 120.

    Cohen, N. R. et al. Innate recognition of cell wall β-glucans drives invariant natural killer T cell responses against fungi. Cell Host Microbe 10, 437–450 (2011).

  121. 121.

    Nakamatsu, M. et al. Role of interferon-γ in Vα14+ natural killer T cell-mediated host defense against Streptococcus pneumoniae infection in murine lungs. Microbes Infect. 9, 364–374 (2007).

  122. 122.

    Nieuwenhuis, E. E. S. et al. CD1d-dependent macrophage-mediated clearance of Pseudomonas aeruginosa from lung. Nat. Med. 8, 588–593 (2002).

  123. 123.

    De Santo, C. et al. Invariant NKT cells reduce the immunosuppressive activity of influenza A virus-induced myeloid-derived suppressor cells in mice and humans. J. Clin. Invest. 118, 4036–4048 (2008).

  124. 124.

    Paget, C. et al. Potential role of invariant NKT cells in the control of pulmonary inflammation and CD8+ T cell response during acute influenza A Virus H3N2 pneumonia. J. Immunol. 186, 5590–5602 (2011).

  125. 125.

    Kok, W. L. et al. Pivotal advance: invariant NKT cells reduce accumulation of inflammatory monocytes in the lungs and decrease immune-pathology during severe influenza A virus infection. J. Leukocyte Biol. 91, 357–368 (2012).

  126. 126.

    Barthelemy, A. et al. Influenza A virus-induced release of interleukin-10 inhibits the anti-microbial activities of invariant natural killer T cells during invasive pneumococcal superinfection. Mucosal Immunol. 10, 460–469 (2017).

  127. 127.

    Ivanov, S. et al. Interleukin-22 reduces lung inflammation during influenza A virus infection and protects against secondary bacterial infection. J. Virol. 87, 6911–6924 (2013).

  128. 128.

    Tsao, C.-C., Tsao, P.-N., Chen, Y.-G. & Chuang, Y.-H. Repeated activation of lung invariant NKT cells results in chronic obstructive pulmonary disease-like symptoms. PLOS One 11, e0147710 (2016).

  129. 129.

    Akbari, O. et al. ICOS/ICOSL interaction is required for CD4+ invariant NKT cell function and homeostatic survival. J. Immunol. 180, 5448–5456 (2008).

  130. 130.

    Akbari, O. et al. Essential role of NKT cells producing IL-4 and IL-13 in the development of allergen-induced airway hyperreactivity. Nat. Med. 9, 582–588 (2003). The data from this study show that iNKT cell production of IL-4 and IL-13 is required for induction of airway hyper reactivity.

  131. 131.

    Lisbonne, M. et al. Cutting edge: invariant Vα14 NKT cells are required for allergen-induced airway inflammation and hyperreactivity in an experimental asthma model. J. Immunol. 171, 1637–1641 (2003).

  132. 132.

    Lee, K.-A. et al. A distinct subset of natural killer T cells produces IL-17, contributing to airway infiltration of neutrophils but not to airway hyperreactivity. Cell. Immunol. 251, 50–55 (2008).

  133. 133.

    Michel, M.-L. et al. Identification of an IL-17-producing NK1.1neg iNKT cell population involved in airway neutrophilia. J. Exp. Med. 204, 995–1001 (2007). References 132 and 133 identify an IL-17-producing iNKT cell subset.

  134. 134.

    Bilenki, L., Yang, J., Fan, Y., Wang, S. & Yang, X. Natural killer T cells contribute to airway eosinophilic inflammation induced by ragweed through enhanced IL-4 and eotaxin production. Eur. J. Immunol. 34, 345–354 (2004).

  135. 135.

    Kim, H. Y. et al. The development of airway hyperreactivity in T-bet-deficient mice requires CD1d-restricted NKT cells. J. Immunol. 182, 3252–3261 (2009).

  136. 136.

    Pichavant, M. et al. Ozone exposure in a mouse model induces airway hyperreactivity that requires the presence of natural killer T cells and IL-17. J. Exp. Med. 205, 385–393 (2008).

  137. 137.

    Wingender, G. et al. Invariant NKT cells are required for airway inflammation induced by environmental antigens. J. Exp. Med. 208, 1151–1162 (2011).

  138. 138.

    Pichavant, M. et al. Oxidative stress-mediated iNKT-cell activation is involved in COPD pathogenesis. Mucosal Immunol. 7, 568–578 (2014).

  139. 139.

    Kim, E. Y. et al. Persistent activation of an innate immune response translates respiratory viral infection into chronic lung disease. Nat. Med. 14, 633–640 (2008).

  140. 140.

    McKnight, C. G. et al. NKT cells contribute to basal IL-4 production but are not required to induce experimental asthma. PLOS One 12, e0188221 (2017).

  141. 141.

    Olszak, T. et al. Microbial exposure during early life has persistent effects on natural killer T cell function. Science 336, 489–493 (2012). This study shows an accumulation of lung and colon NKT cells in germ-free mice and increased morbidity in IBD and asthma models when there is an absence of commensal bacteria in the early life.

  142. 142.

    Akbari, O. et al. CD4+ invariant T-cell-receptor+ natural killer T cells in bronchial asthma. N. Engl. J. Med. 354, 1117–1129 (2006).

  143. 143.

    Vijayanand, P. et al. Invariant natural killer T cells in asthma and chronic obstructive pulmonary disease. N. Engl. J. Med. 356, 1410–1422 (2007).

  144. 144.

    Lynch, L., Nowak, M., Varghese, B., Clark, J. & Hogan, A. E. Adipose tissue invariant NKT cells protect against diet-induced obesity and metabolic disorder through regulatory cytokine production. Immunity (2012).

  145. 145.

    Lynch, L. et al. Invariant NKT cells and CD1d+ cells amass in human omentum and are depleted in patients with cancer and obesity. Eur. J. Immunol. 39, 1893–1901 (2009).

  146. 146.

    Huh, J. Y. et al. A novel function of adipocytes in lipid antigen presentation to iNKT cells. Mol. Cell. Biol. 33, 328–339 (2013).

  147. 147.

    Lynch, L. et al. iNKT cells induce FGF21 for thermogenesis and are required for maximal weight loss in GLP1 therapy. Cell Metab. 24, 510–519 (2016). This study provides a demonstration that iNKT cells induce the browning of white fat and regulate metabolism.

  148. 148.

    Kondo, T., Toyoshima, Y., Ishii, Y. & Kyuwa, S. Natural killer T cells in adipose tissue are activated in lean mice. Exp. Anim. 62, 319–328 (2013).

  149. 149.

    Zhang, H. et al. M2-specific reduction of CD1d switches NKT cell-mediated immune responses and triggers metaflammation in adipose tissue. Cell. Mol. Immunol. (2017).

  150. 150.

    Birkholz, A. M. et al. A novel glycolipid antigen for NKT cells that preferentially induces IFN-γ production. J. Immunol. 195, 924–933 (2015).

  151. 151.

    Ji, Y. et al. 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, 13561–13571 (2012).

  152. 152.

    Schipper, H. S. et al. Natural killer T cells in adipose tissue prevent insulin resistance. J. Clin. Invest. 122, 3343–3354 (2012).

  153. 153.

    Ji, Y. et al. 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, 24378–24386 (2012).

  154. 154.

    Wu, L. et al. 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, E1143–E1152 (2012).

  155. 155.

    Ohmura, K. et al. Natural killer T cells are involved in adipose tissues inflammation and glucose intolerance in diet-induced obese mice. Arterioscler. Thromb. Vasc. Biol. 30, 193–199 (2009).

  156. 156.

    Mantell, B. S. et al. 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, e19831 (2011).

  157. 157.

    Strodthoff, D. et al. Lack of invariant natural killer T cells affects lipid metabolism in adipose tissue of diet-induced obese mice. Arterioscler. Thromb. Vasc. Biol. 33, 1189–1196 (2013).

  158. 158.

    Kammoun, H. L., Kraakman, M. J. & Febbraio, M. A. Adipose tissue inflammation in glucose metabolism. Rev. Endocr. Metab. Disord. 15, 31–44 (2014).

  159. 159.

    Lumeng, C. N. & Saltiel, A. R. Inflammatory links between obesity and metabolic disease. J. Clin. Invest. 121, 2111–2117 (2011).

  160. 160.

    Weisberg, S. P. et al. Obesity is associated with macrophage accumulation in adipose tissue. J. Clin. Invest. 112, 1796–1808 (2003).

  161. 161.

    Xu, H. et al. Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J. Clin. Invest. 112, 1821–1830 (2003).

  162. 162.

    Huh, J. Y. et al. Deletion of CD1d in adipocytes aggravates adipose tissue inflammation and insulin resistance in obesity. Diabetes 66, 835–847 (2017).

  163. 163.

    Satoh, M. et al. Adipocyte-specific CD1d-deficiency mitigates diet-induced obesity and insulin resistance in mice. Sci. Rep. 6, 28473 (2016).

  164. 164.

    Bannai, M. et al. Abundance of unconventional CD8+ natural killer T cells in the large intestine. Eur. J. Immunol. 31, 3361–3369 (2001).

  165. 165.

    Ishimoto, Y. et al. Age-dependent variation in the proportion and number of intestinal lymphocyte subsets, especially natural killer T cells, double-positive CD4+CD8+ cells and B220+ T cells, in mice. Immunology 113, 371–377 (2004).

  166. 166.

    Wingender, G. & Kronenberg, M. Role of NKT cells in the digestive system. IV. The role of canonical natural killer T cells in mucosal immunity and inflammation. Am. J. Physiol. Gastrointest. Liver Physiol. 294, G1–G8 (2008).

  167. 167.

    Ronet, C. et al. NKT cells are critical for the initiation of an inflammatory bowel response against Toxoplasma gondii. J. Immunol. 175, 899–908 (2005).

  168. 168.

    Loh, L., Ivarsson, M. A., Michaëlsson, J., Sandberg, J. K. & Nixon, D. F. Invariant natural killer T cells developing in the human fetus accumulate and mature in the small intestine. Mucosal Immunol. 7, 1233–1243 (2014).

  169. 169.

    Dowds, C. M., Blumberg, R. S. & Zeissig, S. Control of intestinal homeostasis through crosstalk between natural killer T cells and the intestinal microbiota. Clin. Immunol. 159, 128–133 (2015).

  170. 170.

    Nieuwenhuis, E. E. S. et al. Cd1d-dependent regulation of bacterial colonization in the intestine of mice. J. Clin. Invest. 119, 1241–1250 (2009).

  171. 171.

    Farin, H. F. et al. Paneth cell extrusion and release of antimicrobial products is directly controlled by immune cell-derived IFN-γ. J. Exp. Med. 211, 1393–1405 (2014).

  172. 172.

    Zeissig, S. & Blumberg, R. S. Commensal microbiota and NKT cells in the control of inflammatory diseases at mucosal surfaces. Curr. Opin. Immunol. 25, 690–696 (2013).

  173. 173.

    Wingender, G. et al. Intestinal microbes affect phenotypes and functions of invariant natural killer T cells in mice. Gastroenterology 143, 418–428 (2012).

  174. 174.

    Burrello, C. et al. Short-term oral antibiotics treatment promotes inflammatory activation of colonic invariant natural killer T and conventional CD4+T cells. Front. Med. 5, 21 (2018).

  175. 175.

    Heller, F., Fuss, I. J., Nieuwenhuis, E. E., Blumberg, R. S. & Strober, W. Oxazolone colitis, a Th2 colitis model resembling ulcerative colitis, is mediated by IL-13-producing NK-T cells. Immunity 17, 629–638 (2002).

  176. 176.

    Fuss, I. J. et al. Nonclassical CD1d-restricted NK T cells that produce IL-13 characterize an atypical Th2 response in ulcerative colitis. J. Clin. Invest. 113, 1490–1497 (2004).

  177. 177.

    Wieland Brown, L. C. et al. Production of α-galactosylceramide by a prominent member of the human gut microbiota. PLOS Biol. 11, e1001610 (2013).

  178. 178.

    An, D. et al. Sphingolipids from a symbiotic microbe regulate homeostasis of host intestinal natural killer T cells. Cell 156, 123–133 (2014).

  179. 179.

    Montalvillo, E. et al. Increased intraepithelial Vα24 invariant NKT cells in the celiac duodenum. Nutrients 7, 8960–8976 (2015).

  180. 180.

    Grose, R. H., Cummins, A. G. & Thompson, F. M. Deficiency of invariant natural killer T cells in coeliac disease. Gut 56, 790–795 (2007).

  181. 181.

    Wang, Y. et al. Unique invariant natural killer T cells promote intestinal polyps by suppressing TH1 immunity and promoting regulatory T cells. Mucosal Immunol. 11, 131–143 (2018). This study shows that IL-10 production by intestinal iNKT cells prevents spontaneous polyp formation in mutant mice.

  182. 182.

    Olszak, T. et al. Protective mucosal immunity mediated by epithelial CD1d and IL-10. Nature 509, 497–502 (2014). This study shows an opposite effect of CD1d expression by epithelial and bone marrow cells, with epithelial cells promoting an IL-10-mediated anti-inflammatory response.

  183. 183.

    Porcelli, S. A. The CD1 family: a third lineage of antigen-presenting molecules. Adv. Immunol. 59, 1–98 (1995).

  184. 184.

    Hughes, A. L. Evolutionary origin and diversification of the mammalian CD1 antigen genes. Mol. Biol. Evol. 8, 185–201 (1991).

  185. 185.

    Teyton, L. New directions for natural killer T cells in the immunotherapy of cancer. Front. Immunol. 8, 1480 (2017).

  186. 186.

    Robertson, F. C., Berzofsky, J. A. & Terabe, M. NKT cell networks in the regulation of tumor immunity. Front. Immunol. 5, 543 (2014).

  187. 187.

    Taniguchi, M., Harada, M., Dashtsoodol, N. & Kojo, S. Discovery of NKT cells and development of NKT cell-targeted anti-tumor immunotherapy. Proc. Jpn Acad. Ser. B Phys. Biol. Sci. 91, 292–304 (2015).

  188. 188.

    Fujii, S.-I. et al. NKT cells as an ideal anti-tumor immunotherapeutic. Front. Immunol. 4, 409 (2013).

  189. 189.

    Li, X. et al. Design of a potent CD1d-binding NKT cell ligand as a vaccine adjuvant. Proc. Natl Acad. Sci. USA 107, 13010–13015 (2010).

  190. 190.

    Cerundolo, V., Silk, J. D., Masri, S. H. & Salio, M. Harnessing invariant NKT cells in vaccination strategies. Nat. Rev. Immunol. 9, 28–38 (2009).

  191. 191.

    Carreño, L. J., Kharkwal, S. S. & Porcelli, S. A. Optimizing NKT cell ligands as vaccine adjuvants. Immunotherapy 6, 309–320 (2014).

  192. 192.

    Kharkwal, S. S., Arora, P. & Porcelli, S. A. Glycolipid activators of invariant NKT cells as vaccine adjuvants. Immunogenetics 68, 597–610 (2016).

  193. 193.

    Field, J. J. et al. NNKTT120, an anti-iNKT cell monoclonal antibody, produces rapid and sustained iNKT cell depletion in adults with sickle cell disease. PLOS One 12, e0171067 (2017).

  194. 194.

    Field, J. J. Can selectin and iNKT cell therapies meet the needs of people with sickle cell disease? Hematology Am. Soc. Hematol. Educ. Program 2015, 426–432 (2015).

  195. 195.

    Hongo, D., Tang, X., Zhang, X., Engleman, E. G. & Strober, S. Tolerogenic interactions between CD8+ dendritic cells and NKT cells prevent rejection of bone marrow and organ grafts. Blood 129, 1718–1728 (2017).

  196. 196.

    Mavers, M., Maas-Bauer, K. & Negrin, R. S. Invariant natural killer T cells as suppressors of graft-versus-host disease in allogeneic hematopoietic stem cell transplantation. Front. Immunol. 8, 900 (2017).

  197. 197.

    Berzins, S. P. & Ritchie, D. S. Natural killer T cells: drivers or passengers in preventing human disease? Nat. Rev. Immunol. 14, 640–646 (2014).

  198. 198.

    Dashtsoodol, N. et al. Natural killer T cell-targeted immunotherapy mediating long-term memory responses and strong antitumor activity. Front. Immunol. 8, 1206 (2017).

  199. 199.

    Motohashi, S. et al. A phase I-II study of α-galactosylceramide-pulsed IL-2/GM-CSF-cultured peripheral blood mononuclear cells in patients with advanced and recurrent non-small cell lung cancer. J. Immunol. 182, 2492–2501 (2009).

  200. 200.

    Exley, M. A. et al. Adoptive transfer of invariant NKT cells as immunotherapy for advanced melanoma: a phase i clinical trial. Clin. Cancer Res. 23, 3510–3519 (2017).

  201. 201.

    Rampuria, P. & Lang, M. L. CD1d-dependent expansion of NKT follicular helper cells in vivo and in vitro is a product of cellular proliferation and differentiation. Int. Immunol. 27, 253–263 (2015).

  202. 202.

    Bai, L. et al. Natural killer T (NKT)-B cell interactions promote prolonged antibody responses and long-term memory to pneumococcal capsular polysaccharides. Proc. Natl Acad. Sci. USA 110, 16097–16102 (2013).

  203. 203.

    Kawakami, K. et al. Activation of Vα14+ natural killer T cells by α-galactosylceramide results in development of Th1 response and local host resistance in mice infected with Cryptococcus neoformans. Infect. Immun. 69, 213–220 (2001).

  204. 204.

    Jaiswal, A. K., Sadasivam, M. & Hamad, A. R. A. Syndecan-1-coating of interleukin-17-producing natural killer T cells provides a specific method for their visualization and analysis. World J. Diabetes 8, 130–134 (2017).

Download references


The authors’ work is supported by US National Institutes of Health (NIH) grants AI 71922, AI 92763, AI 105215 and AI 137230. C.M.C. is suqpported by American Lung Association Senior Research Training Fellowship RT-412662. The authors thank their colleagues for many helpful discussions.

Reviewer information

Nature Reviews Immunology thanks P. Brennan, M. Brenner, A. Lehuen and the other anonymous reviewer(s) for their contribution to the peer review of this work.

Author information


  1. La Jolla Institute for Allergy and Immunology, La Jolla, CA, USA

    • Catherine M. Crosby
    •  & Mitchell Kronenberg


  1. Search for Catherine M. Crosby in:

  2. Search for Mitchell Kronenberg in:


Both authors contributed to researching, writing and editing the manuscript.

Competing interests

The authors declare no competing interests.

Corresponding author

Correspondence to Mitchell Kronenberg.


α-Galactosyl ceramide

(αGalCer). A glycosphingolipid that is a specific and highly potent activator of invariant natural killer T cells.

Concanavalin A

(Con A). A mitogenic lectin that stimulates T cell proliferation and activation and has been shown to induce invariant natural killer T cell-activated liver damage.

Myeloid-derived suppressor cells

(MDSCs). A heterogeneous group of myeloid cells that exhibits strong immunosuppressive function.

Visceral adipose tissue

(VAT). Adipose tissue that is located around internal organs in the abdominal cavity. Excess visceral fat has been linked to insulin resistance and other obesity-related diseases.

White adipose tissue

(WAT). White and brown adipose tissues are the two types of adipose tissue found in mammals. WAT is the primary tissue for energy storage and it also serves roles in whole body thermal insulation and endocrine regulation of energy homeostasis.


A metabolically driven, chronic, low-grade inflammation that is manifested by immune cells and adipocytes. This inflammation has been linked to obesity and insulin resistance.

Mucosal-associated invariant T cells

An innate-like T cell type with an invariant T cell receptor α (TCRα) chain that recognizes vitamin B metabolites presented on the MHC class I-like molecule MHC class I-related gene protein (MR1).

About this article

Publication history