Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Invariant natural killer T cells: an innate activation scheme linked to diverse effector functions

Key Points

  • Invariant natural killer T (iNKT) cells are a specialized T cell population that recognizes lipid antigens that are presented by a cell-surface molecule known as CD1d. They have been shown to have important roles in many diverse immune responses.

  • iNKT cells recognize both foreign lipid antigens and self lipid antigens. The T cell receptor (TCR)–lipid–CD1d interaction is similar for both self and foreign lipid antigens, despite the differences that exist in these lipid structures. Strong lipid antigens have a 'lock and key' type of binding, whereas weaker antigens require an 'induced fit' mechanism.

  • The production of lipid self antigens for iNKT cells can be upregulated by antigen-presenting cells (APCs) in response to danger signals, such as Toll-like receptor (TLR) agonists. This provides a mechanism for iNKT cell activation in the absence of foreign lipid antigens.

  • In addition to being activated through their TCRs in response to CD1d-presented lipids, iNKT cells can be activated by indirect stimuli, such as pro-inflammatory cytokines. During many infections, interleukin-12 (IL-12) may have an equally important role to lipid antigens in activating iNKT cells.

  • iNKT cells couple the rapid activation kinetics of innate immune cells with the diverse effector functions of adaptive T cells. Early activation during infection leads to rapid cytokine production in target tissues by polarized iNKT cell subsets.

  • Interactions between iNKT cells and CD1d-expressing APCs lead to bidirectional activation. Cytokines produced by iNKT cells activate and recruit other cell types early during immune responses, while activated APCs direct the ensuing adaptive immune responses. Thus, iNKT cells and their lipid antigens help to orchestrate innate and adaptive immune responses.

Abstract

Invariant natural killer T (iNKT) cells exist in a 'poised effector' state, which enables them to rapidly produce cytokines following activation. Using a nearly monospecific T cell receptor, they recognize self and foreign lipid antigens presented by CD1d in a conserved manner, but their activation can catalyse a spectrum of polarized immune responses. In this Review, we discuss recent advances in our understanding of the innate-like mechanisms underlying iNKT cell activation and describe how lipid antigens, the inflammatory milieu and interactions with other immune cell subsets regulate the functions of iNKT cells in health and disease.

This is a preview of subscription content

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1: Selected iNKT cell lipid antigens and closely related non-antigenic lipids.
Figure 2: The mode of binding for an iNKT cell TCR.
Figure 3: TCR- and cytokine-driven activation of iNKT cells.
Figure 4: iNKT cell subsets.
Figure 5: Interactions between iNKT cells and other leukocytes.
Figure 6: iNKT cells during microbial infection.

References

  1. 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).

    CAS  Article  PubMed  Google Scholar 

  2. Tupin, E., Kinjo, Y. & Kronenberg, M. The unique role of natural killer T cells in the response to microorganisms. Nature Rev. Microbiol. 5, 405–417 (2007).

    CAS  Article  Google Scholar 

  3. Novak, J. & Lehuen, A. Mechanism of regulation of autoimmunity by iNKT cells. Cytokine 53, 263–270 (2011).

    CAS  Article  PubMed  Google Scholar 

  4. Meyer, E. H. DeKruyff, R. H. & Umetsu, D. T. iNKT cells in allergic disease. Curr. Top. Microbiol. Immunol. 314, 269–291 (2007).

    CAS  PubMed  Google Scholar 

  5. Vivier, E., Ugolini, S., Blaise, D., Chabannon, C. & Brossay, L. Targeting natural killer cells and natural killer T cells in cancer. Nature Rev. Immunol. 12, 239–252 (2012).

    CAS  Article  Google Scholar 

  6. Bendelac, A., Savage, P. B. & Teyton, L. The biology of NKT cells. Annu. Rev. Immunol. 25, 297–336 (2007).

    CAS  Article  PubMed  Google Scholar 

  7. Brigl, M. & Brenner, M. B. CD1: antigen presentation and T cell function. Annu. Rev. Immunol. 22, 817–890 (2004).

    CAS  Article  PubMed  Google Scholar 

  8. Cohen, N. R., Garg, S. & Brenner, M. B. Antigen presentation by CD1 lipids, T cells, and NKT cells in microbial immunity. Adv. Immunol. 102, 1–94 (2009).

    CAS  Article  PubMed  Google Scholar 

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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  10. Kronenberg, M. Toward an understanding of NKT cell biology: progress and paradoxes. Annu. Rev. Immunol. 23, 877–900 (2005).

    CAS  Article  PubMed  Google Scholar 

  11. Matsuda, J. L., Mallevaey, T., Scott-Browne, J. & Gapin, L. CD1d-restricted iNKT cells, the 'Swiss-Army knife' of the immune system. Curr. Opin. Immunol. 20, 358–368 (2008).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  12. Godfrey, D. I. & Berzins, S. P. Control points in NKT-cell development. Nature Rev. Immunol. 7, 505–518 (2007).

    CAS  Article  Google Scholar 

  13. Stetson, D. B. et al. Constitutive cytokine mRNAs mark natural killer (NK) and NK T cells poised for rapid effector function. J. Exp. Med. 198, 1069–1076 (2003). This study shows that the constitutive production of cytokine-encoding mRNAs enables iNKT cells to rapidly secrete large amounts of cytokines following activation.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  14. Brigl, M., Bry, L., Kent, S. C., Gumperz, J. E. & Brenner, M. B. Mechanism of CD1d-restricted natural killer T cell activation during microbial infection. Nature Immunol. 4, 1230–1237 (2003). This study defined how iNKT cell reactivity to self lipids combined with the release of pro-inflammatory cytokines from APCs results in iNKT cell activation during infection.

    CAS  Google Scholar 

  15. Nagarajan, N. A. & Kronenberg, M. Invariant NKT cells amplify the innate immune response to lipopolysaccharide. J. Immunol. 178, 2706–2713 (2007).

    CAS  Article  PubMed  Google Scholar 

  16. Paget, C. et al. Activation of invariant NKT cells by Toll-like receptor 9-stimulated dendritic cells requires type I interferon and charged glycosphingolipids. Immunity 27, 597–609 (2007).

    CAS  Article  PubMed  Google Scholar 

  17. Salio, M. et al. Modulation of human natural killer T cell ligands on TLR-mediated antigen-presenting cell activation. Proc. Natl Acad. Sci. USA 104, 20490–20495 (2007). References 16 and 17 show that the enhanced presentation of stimulatory self lipid antigens by APCs in response to microbial stimulation contributes to iNKT cell activation.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  18. Cohen, N. R. et al. Shared and distinct transcriptional programs underlie the hybrid nature of iNKT cells. Nature Immunol. 14, 90–99 (2013).

    CAS  Article  Google Scholar 

  19. Brossay, L. et al. Mouse CD1 is mainly expressed on hemopoietic-derived cells. J. Immunol. 159, 1216–1224 (1997).

    CAS  PubMed  Google Scholar 

  20. Roark, J. H. et al. CD1.1 expression by mouse antigen-presenting cells and marginal zone B cells. J. Immunol. 160, 3121–3127 (1998).

    CAS  PubMed  Google Scholar 

  21. Beckman, E. M. et al. Recognition of a lipid antigen by CD1-restricted αβ+ T cells. Nature 372, 691–694 (1994). This study was the first to show that CD1 molecules present lipids as antigens.

    CAS  Article  PubMed  Google Scholar 

  22. Porcelli, S., Morita, C. T. & Brenner, M. B. CD1b restricts the response of human CD48 T lymphocytes to a microbial antigen. Nature 360, 593–597 (1992).

    CAS  Article  PubMed  Google Scholar 

  23. Dellabona, P., Padovan, E., Casorati, G., Brockhaus, M. & Lanzavecchia, A. An invariant Vα24-JαQ/Vβ11 T cell receptor is expressed in all individuals by clonally expanded CD48 T cells. J. Exp. Med. 180, 1171–1176 (1994).

    CAS  Article  PubMed  Google Scholar 

  24. 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).

    CAS  Article  PubMed  Google Scholar 

  25. Porcelli, S., Yockey, C. E., Brenner, M. B. & Balk, S. P. Analysis of T cell antigen receptor (TCR) expression by human peripheral blood CD4-8- α/β T cells demonstrates preferential use of several V β genes and an invariant TCR α chain. J. Exp. Med. 178, 1–16 (1993).

    CAS  Article  PubMed  Google Scholar 

  26. Bendelac, A. Positive selection of mouse NK1+ T cells by CD1-expressing cortical thymocytes. J. Exp. Med. 182, 2091–2096 (1995).

    CAS  Article  PubMed  Google Scholar 

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

    CAS  Article  PubMed  Google Scholar 

  28. Exley, M., Garcia, J., Balk, S. P. & Porcelli, S. Requirements for CD1d recognition by human invariant Vα24+ CD4-CD8- T cells. J. Exp. Med. 186, 109–120 (1997).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  29. Godfrey, D. I., MacDonald, H. R., Kronenberg, M., Smyth, M. J. & Van Kaer, L. NKT cells: what's in a name? Nature Rev. Immunol. 4, 231–237 (2004). This Review provides an excellent summary and timeline of the early discoveries that defined the iNKT cell field and describes the different NKT cell subsets.

    CAS  Article  Google Scholar 

  30. Kawano, T. et al. CD1d-restricted and TCR-mediated activation of Vα14 NKT cells by glycosylceramides. Science 278, 1626–1629 (1997). This report identified α GalCer as the first lipid antigen for iNKT cells.

    CAS  Article  PubMed  Google Scholar 

  31. Benlagha, K., Weiss, A., Beavis, A., Teyton, L. & Bendelac, A. In vivo identification of glycolipid antigen-specific T cells using fluorescent CD1d tetramers. J. Exp. Med. 191, 1895–1903 (2000).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  32. 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). References 31 and 32 first described the use of α GalCer-loaded CD1d tetramers for the specific identification of mouse iNKT cells.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  33. Dascher, C. C. & Brenner, M. B. Evolutionary constraints on CD1 structure: insights from comparative genomic analysis. Trends Immunol. 24, 412–418 (2003).

    CAS  Article  PubMed  Google Scholar 

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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  35. Behar, S. M., Podrebarac, T. A., Roy, C. J., Wang, C. R. & Brenner, M. B. Diverse TCRs recognize murine CD1. J. Immunol. 162, 161–167 (1999).

    CAS  PubMed  Google Scholar 

  36. Cardell, S. et al. CD1-restricted CD4+ T cells in major histocompatibility complex class II-deficient mice. J. Exp. Med. 182, 993–1004 (1995).

    CAS  Article  PubMed  Google Scholar 

  37. Park, S. H., Roark, J. H. & Bendelac, A. Tissue-specific recognition of mouse CD1 molecules. J. Immunol. 160, 3128–3134 (1998).

    CAS  PubMed  Google Scholar 

  38. Arrenberg, P., Halder, R., Dai, Y., Maricic, I. & Kumar, V. Oligoclonality and innate-like features in the TCR repertoire of type II NKT cells reactive to a β-linked self-glycolipid. Proc. Natl Acad. Sci. USA 107, 10984–10989 (2010).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  39. Park, S. H. et al. The mouse CD1d-restricted repertoire is dominated by a few autoreactive T cell receptor families. J. Exp. Med. 193, 893–904 (2001).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  40. Blomqvist, M. et al. Multiple tissue-specific isoforms of sulfatide activate CD1d-restricted type II NKT cells. Eur. J. Immunol. 39, 1726–1735 (2009).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  41. Jahng, A. et al. Prevention of autoimmunity by targeting a distinct, noninvariant CD1d-reactive T cell population reactive to sulfatide. J. Exp. Med. 199, 947–957 (2004).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  42. Johnston, B., Kim, C. H., Soler, D., Emoto, M. & Butcher, E. C. Differential chemokine responses and homing patterns of murine TCR αβ NKT cell subsets. J. Immunol. 171, 2960–2969 (2003).

    CAS  Article  PubMed  Google Scholar 

  43. Kim, C. H., Johnston, B. & Butcher, E. C. Trafficking machinery of NKT cells: shared and differential chemokine receptor expression among Vα24+Vβ11+ NKT cell subsets with distinct cytokine-producing capacity. Blood 100, 11–16 (2002).

    CAS  Article  PubMed  Google Scholar 

  44. Thomas, S. Y. et al. CD1d-restricted NKT cells express a chemokine receptor profile indicative of Th1-type inflammatory homing cells. J. Immunol. 171, 2571–2580 (2003).

    CAS  Article  PubMed  Google Scholar 

  45. Doisne, J. M. et al. Skin and peripheral lymph node invariant NKT cells are mainly retinoic acid receptor-related orphan receptor γt+ and respond preferentially under inflammatory conditions. J. Immunol. 183, 2142–2149 (2009).

    CAS  Article  PubMed  Google Scholar 

  46. 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 study shows that peripheral iNKT cells are mainly tissue resident and are retained locally owing to constitutive LFA1–ICAM1 interactions as a result of PLZF expression.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Lee, W. Y. et al. An intravascular immune response to Borrelia burgdorferi involves Kupffer cells and iNKT cells. Nature Immunol. 11, 295–302 (2010).

    CAS  Article  Google Scholar 

  49. 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).

    CAS  Article  PubMed  Google Scholar 

  50. Wong, C. H., Jenne, C. N., Lee, W. Y., Leger, C. & Kubes, P. Functional innervation of hepatic iNKT cells is immunosuppressive following stroke. Science 334, 101–105 (2011). This study shows that the activation of iNKT cells by noradrenergic transmitters contributes to systemic immunosuppression following stroke.

    CAS  Article  PubMed  Google Scholar 

  51. 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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  52. 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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  53. 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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  54. Lynch, L. et al. Adipose tissue invariant NKT cells protect against diet-induced obesity and metabolic disorder through regulatory cytokine production. Immunity 37, 574–587 (2012).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  56. 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). References 52–56 describe the role of iNKT cells in diet-induced obesity and the metabolic syndrome.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  57. 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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  58. 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). References 57 and 58 describe the use of α GalCer-loaded CD1d tetramers for the characterization of human iNKT cells.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  59. Montoya, C. J. et al. Characterization of human invariant natural killer T subsets in health and disease using a novel invariant natural killer T cell-clonotypic monoclonal antibody, 6B11. Immunology 122, 1–14 (2007).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  60. Kenna, T. et al. NKT cells from normal and tumor-bearing human livers are phenotypically and functionally distinct from murine NKT cells. J. Immunol. 171, 1775–1779 (2003).

    CAS  Article  PubMed  Google Scholar 

  61. 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).

    CAS  Article  PubMed  Google Scholar 

  62. 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).

    CAS  Article  PubMed  Google Scholar 

  63. Berzins, S. P., Smyth, M. J. & Baxter, A. G. Presumed guilty: natural killer T cell defects and human disease. Nature Rev. Immunol. 11, 131–142 (2011).

    CAS  Article  Google Scholar 

  64. Field, J. J., Nathan, D. G. & Linden, J. Targeting iNKT cells for the treatment of sickle cell disease. Clin. Immunol. 140, 177–183 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  65. Wallace, K. L. et al. NKT cells mediate pulmonary inflammation and dysfunction in murine sickle cell disease through production of IFN-γ and CXCR3 chemokines. Blood 114, 667–676 (2009).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  66. 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 describes a prominent role for the intestinal microbiota in iNKT cell development and function.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  67. Hansen, C. H. et al. Patterns of early gut colonization shape future immune responses of the host. PLoS ONE 7, e34043 (2012).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  68. Chang, Y. J. et al. Influenza infection in suckling mice expands an NKT cell subset that protects against airway hyperreactivity. J. Clin. Invest. 121, 57–69 (2011).

    CAS  Article  PubMed  Google Scholar 

  69. Wei, B. et al. Commensal microbiota and CD8+ T cells shape the formation of invariant NKT cells. J. Immunol. 184, 1218–1226 (2010).

    CAS  Article  PubMed  Google Scholar 

  70. Wingender, G. et al. Intestinal microbes affect phenotypes and functions of invariant natural killer T cells in mice. Gastroenterology 143, 293–296 (2012).

    Article  CAS  Google Scholar 

  71. Yuan, J., Nguyen, C. K., Liu, X., Kanellopoulou, C. & Muljo, S. A. Lin28b reprograms adult bone marrow hematopoietic progenitors to mediate fetal-like lymphopoiesis. Science 335, 1195–1200 (2012).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  72. Kinjo, Y. et al. Recognition of bacterial glycosphingolipids by natural killer T cells. Nature 434, 520–525 (2005).

    CAS  Article  PubMed  Google Scholar 

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

    CAS  Article  PubMed  Google Scholar 

  74. Sriram, V., Du, W., Gervay-Hague, J. & Brutkiewicz, R. R. Cell wall glycosphingolipids of Sphingomonas paucimobilis are CD1d-specific ligands for NKT cells. Eur. J. Immunol. 35, 1692–1701 (2005).

    CAS  Article  PubMed  Google Scholar 

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

    CAS  Article  Google Scholar 

  76. Kinjo, Y. et al. Invariant natural killer T cells recognize glycolipids from pathogenic Gram-positive bacteria. Nature Immunol. 12, 966–974 (2011). References 72–76 describe microbial glycolipid antigens that stimulate most (if not all) iNKT cells.

    CAS  Article  Google Scholar 

  77. Amprey, J. L. et al. A subset of liver NK T cells is activated during Leishmania donovani infection by CD1d-bound lipophosphoglycan. J. Exp. Med. 200, 895–904 (2004).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  78. Lotter, H. et al. Natural killer T cells activated by a lipopeptidophosphoglycan from Entamoeba histolytica are critically important to control amebic liver abscess. PLoS Pathog. 5, e1000434 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Fischer, K. et al. Mycobacterial phosphatidylinositol mannoside is a natural antigen for CD1d-restricted T cells. Proc. Natl Acad. Sci. USA 101, 10685–10690 (2004).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  80. Darmoise, A. et al. Lysosomal α-galactosidase controls the generation of self lipid antigens for natural killer T cells. Immunity 33, 216–228 (2010).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  81. Gapin, L. iNKT cell autoreactivity: what is 'self' and how is it recognized? Nature Rev. Immunol. 10, 272–277 (2010).

    CAS  Article  Google Scholar 

  82. Zhou, D. et al. Lysosomal glycosphingolipid recognition by NKT cells. Science 306, 1786–1789 (2004).

    CAS  Article  PubMed  Google Scholar 

  83. Porubsky, S. et al. Normal development and function of invariant natural killer T cells in mice with isoglobotrihexosylceramide (iGb3) deficiency. Proc. Natl Acad. Sci. USA 104, 5977–5982 (2007).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  84. Gadola, S. D. et al. Impaired selection of invariant natural killer T cells in diverse mouse models of glycosphingolipid lysosomal storage diseases. J. Exp. Med. 203, 2293–2303 (2006).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  85. Brennan, P. J. et al. Invariant natural killer T cells recognize lipid self antigen induced by microbial danger signals. Nature Immunol. 12, 1202–1211 (2011). This report characterized β GlcCer as a danger-induced self lipid antigen for iNKT cells.

    CAS  Article  Google Scholar 

  86. Christiansen, D. et al. Humans lack iGb3 due to the absence of functional iGb3-synthase: implications for NKT cell development and transplantation. PLoS Biol. 6, e172 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Cox, D. et al. Determination of cellular lipids bound to human CD1d molecules. PLoS ONE 4, e5325 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Haig, N. A. et al. Identification of self-lipids presented by CD1c and CD1d proteins. J. Biol. Chem. 286, 37692–37701 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  89. Muindi, K. et al. Activation state and intracellular trafficking contribute to the repertoire of endogenous glycosphingolipids presented by CD1d. Proc. Natl Acad. Sci. USA 107, 3052–3057 (2010).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  90. Yuan, W., Kang, S. J., Evans, J. E. & Cresswell, P. Natural lipid ligands associated with human CD1d targeted to different subcellular compartments. J. Immunol. 182, 4784–4791 (2009).

    CAS  Article  PubMed  Google Scholar 

  91. Fox, L. M. et al. Recognition of lyso-phospholipids by human natural killer T lymphocytes. PLoS Biol. 7, e1000228 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Pei, B. et al. Diverse endogenous antigens for mouse NKT cells: self-antigens that are not glycosphingolipids. J. Immunol. 186, 1348–1360 (2011).

    CAS  Article  PubMed  Google Scholar 

  93. Ortaldo, J. R. et al. Dissociation of NKT stimulation, cytokine induction, and NK activation in vivo by the use of distinct TCR-binding ceramides. J. Immunol. 172, 943–953 (2004).

    CAS  Article  PubMed  Google Scholar 

  94. Parekh, V. V. et al. Quantitative and qualitative differences in the in vivo response of NKT cells to distinct α- and β-anomeric glycolipids. J. Immunol. 173, 3693–3706 (2004).

    CAS  Article  PubMed  Google Scholar 

  95. Stanic, A. K. et al. Defective presentation of the CD1d1-restricted natural Va14Ja18 NKT lymphocyte antigen caused by β-D-glucosylceramide synthase deficiency. Proc. Natl Acad. Sci. USA 100, 1849–1854 (2003).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  96. Margalit, M. et al. Glucocerebroside treatment ameliorates ConA hepatitis by inhibition of NKT lymphocytes. Am. J. Physiol. Gastrointest. Liver Physiol. 289, G917–G925 (2005).

    CAS  Article  PubMed  Google Scholar 

  97. Wu, D. Y., Segal, N. H., Sidobre, S., Kronenberg, M. & Chapman, P. B. Cross-presentation of disialoganglioside GD3 to natural killer T cells. J. Exp. Med. 198, 173–181 (2003).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  98. Facciotti, F. et al. Peroxisome-derived lipids are self antigens that stimulate invariant natural killer T cells in the thymus. Nature Immunol. 13, 474–480 (2012). This study describes peroxisome-derived plasmalogens as self antigens that stimulate iNKT cells in the thymus and thereby contribute to iNKT cell development.

    CAS  Article  Google Scholar 

  99. Girardi, E. et al. Unique interplay between sugar and lipid in determining the antigenic potency of bacterial antigens for NKT cells. PLoS Biol. 9, e1001189 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  100. McCarthy, C. et al. The length of lipids bound to human CD1d molecules modulates the affinity of NKT cell TCR and the threshold of NKT cell activation. J. Exp. Med. 204, 1131–1144 (2007).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  101. Wun, K. S. et al. A molecular basis for the exquisite CD1d-restricted antigen specificity and functional responses of natural killer T cells. Immunity 34, 327–339 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  102. Yu, K. O. et al. Modulation of CD1d-restricted NKT cell responses by using N-acyl variants of α-galactosylceramides. Proc. Natl Acad. Sci. USA 102, 3383–3388 (2005).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  103. Koch, M. et al. The crystal structure of human CD1d with and without α-galactosylceramide. Nature Immunol. 6, 819–826 (2005).

    CAS  Article  Google Scholar 

  104. Zajonc, D. M. et al. Structure and function of a potent agonist for the semi-invariant natural killer T cell receptor. Nature Immunol. 6, 810–818 (2005).

    CAS  Article  Google Scholar 

  105. Borg, N. A. et al. CD1d–lipid–antigen recognition by the semi-invariant NKT T-cell receptor. Nature 448, 44–49 (2007). This study describes the structure of the trimolecular TCR– α GalCer–CD1d complex and defines the unique mode of antigen recognition by iNKT cells, which is distinct from the recognition of peptide–MHC complexes.

    CAS  Article  PubMed  Google Scholar 

  106. Mallevaey, T. et al. A molecular basis for NKT cell recognition of CD1d–self-antigen. Immunity 34, 315–326 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  107. Matulis, G. et al. Innate-like control of human iNKT cell autoreactivity via the hypervariable CDR3β loop. PLoS Biol. 8, e1000402 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Wun, K. S. et al. A minimal binding footprint on CD1d–glycolipid is a basis for selection of the unique human NKT TCR. J. Exp. Med. 205, 939–949 (2008).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  109. Uldrich, A. P. et al. A semi-invariant Vα10+ T cell antigen receptor defines a population of natural killer T cells with distinct glycolipid antigen-recognition properties. Nature Immunol. 12, 616–623 (2011).

    CAS  Article  Google Scholar 

  110. Brigl, M. et al. Conserved and heterogeneous lipid antigen specificities of CD1d-restricted NKT cell receptors. J. Immunol. 176, 3625–3634 (2006).

    CAS  Article  PubMed  Google Scholar 

  111. Gadola, S. D., Dulphy, N., Salio, M. & Cerundolo, V. Vα24-JαQ-independent, CD1d-restricted recognition of α-galactosylceramide by human CD4+ and CD8αβ+ T lymphocytes. J. Immunol. 168, 5514–5520 (2002).

    CAS  Article  PubMed  Google Scholar 

  112. Lopez-Sagaseta, J., Kung, J. E., Savage, P. B., Gumperz, J. & Adams, E. J. The molecular basis for recognition of CD1d/α-galactosylceramide by a human non-Vα24 T cell receptor. PLoS Biol. 10, e1001412 (2012).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  113. Scott-Browne, J. P. et al. Germline-encoded recognition of diverse glycolipids by natural killer T cells. Nature Immunol. 8, 1105–1113 (2007).

    CAS  Article  Google Scholar 

  114. Li, Y. et al. The Vα14 invariant natural killer T cell TCR forces microbial glycolipids and CD1d into a conserved binding mode. J. Exp. Med. 207, 2383–2393 (2010).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  115. Pellicci, D. G. et al. Recognition of β-linked self glycolipids mediated by natural killer T cell antigen receptors. Nature Immunol. 12, 827–833 (2011).

    CAS  Article  Google Scholar 

  116. Yu, E. D., Girardi, E., Wang, J. & Zajonc, D. M. Cutting edge: structural basis for the recognition of β-linked glycolipid antigens by invariant NKT cells. J. Immunol. 187, 2079–2083 (2011). References 115 and 116 show how β -linked self lipids can be recognized by the iNKT cell TCR.

    CAS  Article  PubMed  Google Scholar 

  117. Lopez-Sagaseta, J., Sibener, L. V., Kung, J. E., Gumperz, J. & Adams, E. J. Lysophospholipid presentation by CD1d and recognition by a human natural killer T-cell receptor. EMBO J. 31, 2047–2059 (2012).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  118. Girardi, E. et al. Type II natural killer T cells use features of both innate-like and conventional T cells to recognize sulfatide self antigens. Nature Immunol. 13, 851–856 (2012).

    CAS  Article  Google Scholar 

  119. Patel, O. et al. Recognition of CD1d–sulfatide mediated by a type II natural killer T cell antigen receptor. Nature Immunol. 13, 857–863 (2012).

    CAS  Article  Google Scholar 

  120. Rossjohn, J., Pellicci, D. G., Patel, O., Gapin, L. & Godfrey, D. I. Recognition of CD1d-restricted antigens by natural killer T cells. Nature Rev. Immunol. 12, 845–857 (2012).

    CAS  Article  Google Scholar 

  121. Kitamura, H. et al. The natural killer T (NKT) cell ligand α-galactosylceramide demonstrates its immunopotentiating effect by inducing interleukin (IL)-12 production by dendritic cells and IL-12 receptor expression on NKT cells. J. Exp. Med. 189, 1121–1128 (1999). This study demonstrated bidirectional activation between iNKT cells and APCs.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  122. Leite-De-Moraes, M. C. et al. A distinct IL-18-induced pathway to fully activate NK T lymphocytes independently from TCR engagement. J. Immunol. 163, 5871–5876 (1999).

    CAS  PubMed  Google Scholar 

  123. Rachitskaya, A. V. et al. Cutting edge: NKT cells constitutively express IL-23 receptor and RORγt and rapidly produce IL-17 upon receptor ligation in an IL-6-independent fashion. J. Immunol. 180, 5167–5171 (2008).

    CAS  Article  PubMed  Google Scholar 

  124. Stock, P., Lombardi, V., Kohlrautz, V. & Akbari, O. Induction of airway hyperreactivity by IL-25 is dependent on a subset of invariant NKT cells expressing IL-17RB. J. Immunol. 182, 5116–5122 (2009).

    CAS  Article  PubMed  Google Scholar 

  125. Terashima, A. et al. A novel subset of mouse NKT cells bearing the IL-17 receptor B responds to IL-25 and contributes to airway hyperreactivity. J. Exp. Med. 205, 2727–2733 (2008).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  126. Wesley, J. D., Tessmer, M. S., Chaukos, D. & Brossay, L. NK cell-like behavior of Vα14i NK T cells during MCMV infection. PLoS Pathog. 4, e1000106 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. 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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  128. 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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  129. 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). This study describes how stimulation with self lipid antigens alters the acetylation of cytokine gene loci, enabling iNKT cell responsiveness to stimulation with IL-12 and IL-18.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  130. Bendelac, A. Mouse NK1+ T cells. Curr. Opin. Immunol. 7, 367–374 (1995).

    CAS  Article  PubMed  Google Scholar 

  131. Makino, Y., Kanno, R., Ito, T., Higashino, K. & Taniguchi, M. Predominant expression of invariant Vα14+ TCR α chain in NK1.1+ T cell populations. Int. Immunol. 7, 1157–1161 (1995).

    CAS  Article  PubMed  Google Scholar 

  132. Skold, M. & Cardell, S. Differential regulation of Ly49 expression on CD4+ and CD4CD8 (double negative) NK1.1+ T cells. Eur. J. Immunol. 30, 2488–2496 (2000).

    CAS  Article  PubMed  Google Scholar 

  133. Arase, H., Arase, N. & Saito, T. Interferon γ production by natural killer (NK) cells and NK1.1+ T cells upon NKR-P1 cross-linking. J. Exp. Med. 183, 2391–2396 (1996).

    CAS  Article  PubMed  Google Scholar 

  134. Germain, C. et al. Induction of lectin-like transcript 1 (LLT1) protein cell surface expression by pathogens and interferon-γ contributes to modulate immune responses. J. Biol. Chem. 286, 37964–37975 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  135. Champsaur, M. & Lanier, L. L. Effect of NKG2D ligand expression on host immune responses. Immunol. Rev. 235, 267–285 (2010).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  136. Kuylenstierna, C. et al. NKG2D performs two functions in invariant NKT cells: direct TCR-independent activation of NK-like cytolysis and co-stimulation of activation by CD1d. Eur. J. Immunol. 41, 1913–1923 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  137. Maeda, M., Lohwasser, S., Yamamura, T. & Takei, F. Regulation of NKT cells by Ly49: analysis of primary NKT cells and generation of NKT cell line. J. Immunol. 167, 4180–4186 (2001).

    CAS  Article  PubMed  Google Scholar 

  138. Skold, M. et al. MHC-dependent and -independent modulation of endogenous Ly49 receptors on NK1.1+ T lymphocytes directed by T-cell receptor type. Immunology 110, 313–321 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Lee, H. H. et al. Apoptotic cells activate NKT cells through T cell Ig-like mucin-like-1 resulting in airway hyperreactivity. J. Immunol. 185, 5225–5235 (2010).

    CAS  Article  PubMed  Google Scholar 

  140. 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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  141. Nowak, M. et al. The A2aR adenosine receptor controls cytokine production in iNKT cells. Eur. J. Immunol. 40, 682–687 (2010).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  142. Miyamoto, K., Miyake, S. & Yamamura, T. A synthetic glycolipid prevents autoimmune encephalomyelitis by inducing TH2 bias of natural killer T cells. Nature 413, 531–534 (2001).

    CAS  Article  PubMed  Google Scholar 

  143. Schmieg, J., Yang, G., Franck, R. W. & Tsuji, M. Superior protection against malaria and melanoma metastases by a C-glycoside analogue of the natural killer T cell ligand α-galactosylceramide. J. Exp. Med. 198, 1631–1641 (2003).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  144. Sullivan, B. A. et al. Mechanisms for glycolipid antigen-driven cytokine polarization by Vα14i NKT cells. J. Immunol. 184, 141–153 (2010).

    CAS  Article  PubMed  Google Scholar 

  145. Bai, L. et al. Distinct APCs explain the cytokine bias of α-galactosylceramide variants in vivo. J. Immunol. 188, 3053–3061 (2012).

    CAS  Article  PubMed  Google Scholar 

  146. Im, J. S. et al. Kinetics and cellular site of glycolipid loading control the outcome of natural killer T cell activation. Immunity 30, 888–898 (2009). This study shows that the manner in which different lipids are loaded onto CD1d can determine the outcome of iNKT cell activation.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  147. Coquet, J. M. et al. Diverse cytokine production by NKT cell subsets and identification of an IL-17-producing CD4NK1.1 NKT cell population. Proc. Natl Acad. Sci. USA 105, 11287–11292 (2008). This study provided important information on the diversity and extent of cytokine production by iNKT cell subsets.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  148. Takahashi, T. et al. Cutting edge: analysis of human Vα24+CD8+ NK T cells activated by α-galactosylceramide-pulsed monocyte-derived dendritic cells. J. Immunol. 168, 3140–3144 (2002).

    CAS  Article  PubMed  Google Scholar 

  149. O'Reilly, V. et al. Distinct and overlapping effector functions of expanded human CD4+, CD8α+ and CD4CD8α invariant natural killer T cells. PLoS ONE 6, e28648 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  150. Hammond, K. J. et al. CD1d-restricted NKT cells: an interstrain comparison. J. Immunol. 167, 1164–1173 (2001).

    CAS  Article  PubMed  Google Scholar 

  151. Watarai, H. et al. Development and function of invariant natural killer T cells producing Th2- and Th17-cytokines. PLoS Biol. 10, e1001255 (2012). This report is a comprehensive analysis of mouse iNKT cell functional subsets.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  152. 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).

    CAS  Article  PubMed  Google Scholar 

  153. Kim, P. J. et al. GATA-3 regulates the development and function of invariant NKT cells. J. Immunol. 177, 6650–6659 (2006).

    CAS  Article  PubMed  Google Scholar 

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

    CAS  Article  Google Scholar 

  155. 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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  156. 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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  157. Michel, M. L. et al. Critical role of ROR-γt in a new thymic pathway leading to IL-17-producing invariant NKT cell differentiation. Proc. Natl Acad. Sci. USA 105, 19845–19850 (2008).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  158. 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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

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

    CAS  Article  PubMed  Google Scholar 

  160. Snyder-Cappione, J. E. et al. A comprehensive ex vivo functional analysis of human NKT cells reveals production of MIP1-α and MIP1-β, a lack of IL-17, and a Th1-bias in males. PLoS ONE 5, e15412 (2010).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  161. Chang, P. P. et al. Identification of Bcl-6-dependent follicular helper NKT cells that provide cognate help for B cell responses. Nature Immunol. 13, 35–43 (2012).

    CAS  Article  Google Scholar 

  162. King, I. L. et al. Invariant natural killer T cells direct B cell responses to cognate lipid antigen in an IL-21-dependent manner. Nature Immunol. 13, 44–50 (2012).

    CAS  Article  Google Scholar 

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

    CAS  Article  PubMed  Google Scholar 

  164. Bosma, A., Abdel-Gadir, A., Isenberg, D. A., Jury, E. C. & Mauri, C. Lipid-antigen presentation by CD1d+ B cells is essential for the maintenance of invariant natural killer T cells. Immunity 36, 477–490 (2012).

    CAS  Article  PubMed  Google Scholar 

  165. Barral, P., Sanchez-Nino, M. D., van Rooijen, N., Cerundolo, V. & Batista, F. D. The location of splenic NKT cells favours their rapid activation by blood-borne antigen. EMBO J. 31, 2378–2390 (2012).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  166. Fujii, S., Liu, K., Smith, C., Bonito, A. J. & Steinman, R. M. 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, 1607–1618 (2004).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  167. Fujii, S., Shimizu, K., Kronenberg, M. & Steinman, R. M. Prolonged IFN-γ-producing NKT response induced with α-galactosylceramide-loaded DCs. Nature Immunol. 3, 867–874 (2002).

    CAS  Article  Google Scholar 

  168. Bezbradica, J. S. et al. Distinct roles of dendritic cells and B cells in Va14Ja18 natural T cell activation in vivo. J. Immunol. 174, 4696–4705 (2005).

    CAS  Article  PubMed  Google Scholar 

  169. van den Elzen, P. et al. Apolipoprotein-mediated pathways of lipid antigen presentation. Nature 437, 906–910 (2005).

    CAS  Article  PubMed  Google Scholar 

  170. Carnaud, C. et al. Cutting edge: cross-talk between cells of the innate immune system: NKT cells rapidly activate NK cells. J. Immunol. 163, 4647–4650 (1999). This study defined the transactivation of NK cells and B cells following iNKT cell activation.

    CAS  PubMed  Google Scholar 

  171. Fujii, S., Shimizu, K., Smith, C., Bonifaz, L. & Steinman, R. M. Activation of natural killer T cells by α-galactosylceramide rapidly induces the full maturation of dendritic cells in vivo and thereby acts as an adjuvant for combined CD4 and CD8 T cell immunity to a coadministered protein. J. Exp. Med. 198, 267–279 (2003).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  172. Hermans, I. F. et al. NKT cells enhance CD4+ and CD8+ T cell responses to soluble antigen in vivo through direct interaction with dendritic cells. J. Immunol. 171, 5140–5147 (2003).

    CAS  Article  PubMed  Google Scholar 

  173. Semmling, V. et al. Alternative cross-priming through CCL17–CCR4-mediated attraction of CTLs toward NKT cell-licensed DCs. Nature Immunol. 11, 313–320 (2010).

    CAS  Article  Google Scholar 

  174. Gonzalez-Aseguinolaza, G. et al. Natural killer T cell ligand α-galactosylceramide enhances protective immunity induced by malaria vaccines. J. Exp. Med. 195, 617–624 (2002).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  175. Silk, J. D. et al. Utilizing the adjuvant properties of CD1d-dependent NK T cells in T cell-mediated immunotherapy. J. Clin. Invest. 114, 1800–1811 (2004).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  176. Bialecki, E. et al. Role of marginal zone B lymphocytes in invariant NKT cell activation. J. Immunol. 182, 6105–6113 (2009).

    CAS  Article  PubMed  Google Scholar 

  177. Zietara, N., Lyszkiewicz, M., Krueger, A. & Weiss, S. ICOS-dependent stimulation of NKT cells by marginal zone B cells. Eur. J. Immunol. 41, 3125–3134 (2011).

    CAS  Article  PubMed  Google Scholar 

  178. Leadbetter, E. A. et al. NK T cells provide lipid antigen-specific cognate help for B cells. Proc. Natl Acad. Sci. USA 105, 8339–8344 (2008).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  179. Galli, G. et al. CD1d-restricted help to B cells by human invariant natural killer T lymphocytes. J. Exp. Med. 197, 1051–1057 (2003).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  180. Galli, G. et al. Invariant NKT cells sustain specific B cell responses and memory. Proc. Natl Acad. Sci. USA 104, 3984–3989 (2007).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  181. Lang, G. A., Devera, T. S. & Lang, M. L. Requirement for CD1d expression by B cells to stimulate NKT cell-enhanced antibody production. Blood 111, 2158–2162 (2008).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  182. Tonti, E. et al. NKT-cell help to B lymphocytes can occur independently of cognate interaction. Blood 113, 370–376 (2009).

    CAS  Article  PubMed  Google Scholar 

  183. Detre, C. et al. SAP expression in invariant NKT cells is required for cognate help to support B-cell responses. Blood 120, 122–129 (2012).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  184. 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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

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

    CAS  Article  Google Scholar 

  186. Vasan, S. & Tsuji, M. A double-edged sword: the role of NKT cells in malaria and HIV infection and immunity. Semin. Immunol. 22, 87–96 (2010). References 185 and 186 are review articles that describe the potential of using pharmacological iNKT cell activation in vaccine strategies.

    CAS  Article  PubMed  Google Scholar 

  187. Schmieg, J., Yang, G., Franck, R. W., Van Rooijen, N. & Tsuji, M. Glycolipid presentation to natural killer T cells differs in an organ-dependent fashion. Proc. Natl Acad. Sci. USA 102, 1127–1132 (2005).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  188. Winau, F. et al. Ito cells are liver-resident antigen-presenting cells for activating T cell responses. Immunity 26, 117–129 (2007).

    CAS  Article  PubMed  Google Scholar 

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

    CAS  Article  Google Scholar 

  190. Nieuwenhuis, E. E. et al. CD1d-dependent macrophage-mediated clearance of Pseudomonas aeruginosa from lung. Nature Med. 8, 588–593 (2002). This report provides an important example of the tissue-specific effector functions of iNKT cells during infection.

    CAS  Article  PubMed  Google Scholar 

  191. Sada-Ovalle, I., Chiba, A., Gonzales, A., Brenner, M. B. & Behar, S. M. Innate invariant NKT cells recognize Mycobacterium tuberculosis-infected macrophages, produce interferon-γ, and kill intracellular bacteria. PLoS Pathog. 4, e1000239 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  Article  PubMed  Google Scholar 

  193. Hegde, S. et al. NKT cells direct monocytes into a DC differentiation pathway. J. Leukoc. Biol. 81, 1224–1235 (2007).

    CAS  Article  PubMed  Google Scholar 

  194. Kotsianidis, I. et al. Regulation of hematopoiesis in vitro and in vivo by invariant NKT cells. Blood 107, 3138–3144 (2006).

    CAS  Article  PubMed  Google Scholar 

  195. Metelitsa, L. S. Anti-tumor potential of type-I NKT cells against CD1d-positive and CD1d-negative tumors in humans. Clin. Immunol. 140, 119–129 (2011).

    CAS  Article  PubMed  Google Scholar 

  196. 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). This study demonstrated a prominent role for iNKT cells during infection.

    CAS  Article  PubMed  Google Scholar 

  197. Li, L. et al. NKT cell activation mediates neutrophil IFN-γ production and renal ischemia–reperfusion injury. J. Immunol. 178, 5899–5911 (2007).

    CAS  Article  PubMed  Google Scholar 

  198. De Santo, C. et al. Invariant NKT cells modulate the suppressive activity of IL-10-secreting neutrophils differentiated with serum amyloid A. Nature Immunol. 11, 1039–1046 (2010).

    CAS  Article  Google Scholar 

  199. Wingender, G. et al. Neutrophilic granulocytes modulate invariant NKT cell function in mice and humans. J. Immunol. 188, 3000–3008 (2012).

    CAS  Article  PubMed  Google Scholar 

  200. Kobrynski, L. J., Sousa, A. O., Nahmias, A. J. & Lee, F. K. Cutting edge: antibody production to pneumococcal polysaccharides requires CD1 molecules and CD8+ T cells. J. Immunol. 174, 1787–1790 (2005).

    CAS  Article  PubMed  Google Scholar 

  201. 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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  202. 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).

    CAS  Article  PubMed  Google Scholar 

  203. Guillonneau, C. et al. Combined NKT cell activation and influenza virus vaccination boosts memory CTL generation and protective immunity. Proc. Natl Acad. Sci. USA 106, 3330–3335 (2009).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  204. Ho, L. P. et al. Activation of invariant NKT cells enhances the innate immune response and improves the disease course in influenza A virus infection. Eur. J. Immunol. 38, 1913–1922 (2008).

    CAS  Article  PubMed  Google Scholar 

  205. 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. Leukoc. Biol. 91, 357–368 (2012).

    CAS  Article  PubMed  Google Scholar 

  206. Akbari, O. et al. Essential role of NKT cells producing IL-4 and IL-13 in the development of allergen-induced airway hyperreactivity. Nature Med. 9, 582–588 (2003). This report demonstrated an important role for iNKT cells in airway hyperresponsiveness.

    CAS  Article  PubMed  Google Scholar 

  207. 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).

    CAS  Article  PubMed  Google Scholar 

  208. Meyer, E. H. et al. Glycolipid activation of invariant T cell receptor+ NK T cells is sufficient to induce airway hyperreactivity independent of conventional CD4+ T cells. Proc. Natl Acad. Sci. USA 103, 2782–2787 (2006).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  209. D'Cruz, L. M., Yang, C. Y. & Goldrath, A. W. Transcriptional regulation of NKT cell development and homeostasis. Curr. Opin. Immunol. 22, 199–205 (2010).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

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

    CAS  Article  Google Scholar 

  211. Dao, T. et al. Development of CD1d-restricted NKT cells in the mouse thymus. Eur. J. Immunol. 34, 3542–3552 (2004).

    CAS  Article  PubMed  Google Scholar 

  212. Egawa, T. et al. Genetic evidence supporting selection of the Vα14i NKT cell lineage from double-positive thymocyte precursors. Immunity 22, 705–716 (2005).

    CAS  Article  PubMed  Google Scholar 

  213. Gapin, L., Matsuda, J. L., Surh, C. D. & Kronenberg, M. NKT cells derive from double-positive thymocytes that are positively selected by CD1d. Nature Immunol. 2, 971–978 (2001).

    CAS  Article  Google Scholar 

  214. Coles, M. C. & Raulet, D. H. Class I dependence of the development of CD4+ CD8 NK1.1+ thymocytes. J. Exp. Med. 180, 395–399 (1994).

    CAS  Article  PubMed  Google Scholar 

  215. 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).

    CAS  Article  PubMed  Google Scholar 

  216. Moran, A. E. et al. T cell receptor signal strength in Treg and iNKT cell development demonstrated by a novel fluorescent reporter mouse. J. Exp. Med. 208, 1279–1289 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  217. Seiler, M. P. et al. Elevated and sustained expression of the transcription factors Egr1 and Egr2 controls NKT lineage differentiation in response to TCR signaling. Nature Immunol. 13, 264–271 (2012).

    CAS  Article  Google Scholar 

  218. Kovalovsky, D. et al. The BTB-zinc finger transcriptional regulator PLZF controls the development of invariant natural killer T cell effector functions. Nature Immunol. 9, 1055–1064 (2008).

    CAS  Article  Google Scholar 

  219. Savage, A. K. et al. The transcription factor PLZF directs the effector program of the NKT cell lineage. Immunity 29, 391–403 (2008). References 218 and 219 describe the crucial role of the transcription factor PLZF in iNKT cell lineage determination.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  220. Mathew, R. et al. BTB-ZF factors recruit the E3 ligase cullin 3 to regulate lymphoid effector programs. Nature 491, 618–621 (2012).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  221. Kovalovsky, D. et al. PLZF induces the spontaneous acquisition of memory/effector functions in T cells independently of NKT cell-related signals. J. Immunol. 184, 6746–6755 (2010).

    CAS  Article  PubMed  Google Scholar 

  222. Raberger, J. et al. The transcriptional regulator PLZF induces the development of CD44 high memory phenotype T cells. Proc. Natl Acad. Sci. USA 105, 17919–17924 (2008).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  223. Savage, A. K., Constantinides, M. G. & Bendelac, A. Promyelocytic leukemia zinc finger turns on the effector T cell program without requirement for agonist TCR signaling. J. Immunol. 186, 5801–5806 (2011).

    CAS  Article  PubMed  Google Scholar 

  224. Griewank, K. et al. Homotypic interactions mediated by Slamf1 and Slamf6 receptors control NKT cell lineage development. Immunity 27, 751–762 (2007).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  225. Kageyama, R. et al. The receptor Ly108 functions as a SAP adaptor-dependent on-off switch for T cell help to B cells and NKT cell development. Immunity 36, 986–1002 (2012).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  226. Benlagha, K., Kyin, T., Beavis, A., Teyton, L. & Bendelac, A. A thymic precursor to the NK T cell lineage. Science 296, 553–555 (2002).

    CAS  Article  PubMed  Google Scholar 

  227. Benlagha, K., Wei, D. G., Veiga, J., Teyton, L. & Bendelac, A. Characterization of the early stages of thymic NKT cell development. J. Exp. Med. 202, 485–492 (2005).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  228. Gadue, P. & Stein, P. L. NKT cell precursors exhibit differential cytokine regulation and require Itk for efficient maturation. J. Immunol. 169, 2397–2406 (2002).

    CAS  Article  PubMed  Google Scholar 

  229. 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).

    CAS  Article  PubMed  Google Scholar 

  230. Matangkasombut, P., Pichavant, M., Dekruyff, R. H. & Umetsu, D. T. Natural killer T cells and the regulation of asthma. Mucosal Immunol. 2, 383–392 (2009).

    CAS  Article  PubMed  Google Scholar 

  231. Lukens, J. R. & Kanneganti, T. D. Fat chance: not much against NKT cells. Immunity 37, 447–449 (2012).

    CAS  Article  PubMed  Google Scholar 

  232. Hammond, K. J. & Kronenberg, M. Natural killer T cells: natural or unnatural regulators of autoimmunity? Curr. Opin. Immunol. 15, 683–689 (2003).

    CAS  Article  PubMed  Google Scholar 

  233. Tatituri, R. V. et al. Recognition of microbial and mammalian phospholipid antigens by NKT cells with diverse TCRs. Proc. Natl Acad. Sci. USA (in the press).

  234. Tyznik, A. J. et al. Cutting edge: the mechanism of invariant NKT cell responses to viral danger signals. J. Immunol. 181, 4452–4456 (2008).

    CAS  Article  PubMed  Google Scholar 

Download references

Acknowledgements

P.J.B. is supported by a career development award from the American Academy of Allergy, Asthma and Immunology ARTrust. M.B. is supported by the US National Institutes of Health (grant AI077795). M.B.B. is supported by research grants from the US National Institutes of Health (AI063428, AI028973 and DK057521) and the American Diabetes Association (7-12-IN-07). We thank R. Tatituri, E. Kim and L. Lynch for helpful discussions during the preparation of this manuscript. We also thank J. Rossjohn for providing the protein crystal structures shown in Fig. 2.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Michael B. Brenner.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Related links

Related links

FURTHER INFORMATION

Michael Brenner's homepage

Glossary

Somatic recombination

(Also known as V(D)J recombination). The somatic rearrangement of variable (V), diversity (D) and joining (J) regions of the genes that encode antigen receptors, leading to repertoire diversity of both T cell and B cell receptors.

Omentum

The folds of peritoneum between the stomach and abdomen that contain lymphoid aggregates known as 'milky spots'.

Sickle cell disease

An inherited disorder of erythrocytes, with a high prevalence in African and African American populations, that is caused by a mutation in the β-globin gene. A single nucleotide substitution (and the resultant amino-acid substitution) leads to the polymerization of haemoglobin when it is deoxygenated, ultimately resulting in the occlusion of small blood vessels. Disease manifestations include chronic anaemia, multiple painful crises, organ damage and increased susceptibility to bacterial infections.

MicroRNAs

Small RNA molecules that regulate the expression of genes by binding to the 3′-untranslated regions of specific mRNAs.

Gangliosides

A group of glycosphingolipids that are prominent components of nerve cell membranes.

β2-microglobulin

A protein comprising a single immunoglobulin-like domain that non-covalently associates with the main polypeptide chain of MHC class I molecules. In the absence of β2-microglobulin, MHC class I molecules are unstable and are therefore found at very low levels on the cell surface.

Complementarity-determining region 3

(CDR3). The CDRs are the amino-acid sequences of the B cell receptor and the T cell receptor that physically contact the antigen and are the most variable parts of the receptors. There are three such regions — CDR1, CDR2 and CDR3 — in each receptor chain. CDR3 arises from recombination of the variable (V), diversity (D) and joining (J) regions of each receptor chain and is the most variable CDR.

Ischaemia–reperfusion injury

An injury in which the tissue first suffers from hypoxia as a result of severely decreased, or completely arrested, blood flow. The restoration of normal blood flow then triggers inflammation, which exacerbates the tissue damage.

NK cell transactivation

The secondary activation of a natural killer (NK) cell by interleukin-12 (IL-12), which leads to the production of interferon-γ. This process occurs following the primary activation of an IL-12- producing cell type, such as an activated dendritic cell.

Cross-presentation

The ability of certain antigen-presenting cells to load peptides that are derived from exogenous antigens onto MHC class I molecules. This property is atypical, because most cells exclusively present peptides from their endogenous proteins on MHC class I molecules. Cross-presentation is essential for the initiation of immune responses to viruses that do not infect antigen-presenting cells.

M2 macrophages

Macrophages that differentiate in response to interleukin-4 (IL-4) or IL-13 and are thought to mediate T helper 2-type immune responses, such as protection from parasites and wound healing. M2 macrophages are typically defined by their expression of arginase 1, the mannose receptor CD206 and the IL-4 receptor -chain, and they can produce large amounts of IL-10.

Myeloid-derived suppressor cell

(MDSC). A member of a heterogeneous population of immature myeloid cells with immunosuppressive functions. MDSCs can accumulate in tissues during inflammation or in response to tumour-derived cytokines.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Brennan, P., Brigl, M. & Brenner, M. Invariant natural killer T cells: an innate activation scheme linked to diverse effector functions. Nat Rev Immunol 13, 101–117 (2013). https://doi.org/10.1038/nri3369

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nri3369

Further reading

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing