Skip to main content

Advertisement

Log in

Glycolipid activators of invariant NKT cells as vaccine adjuvants

  • Review
  • Published:
Immunogenetics Aims and scope Submit manuscript

Abstract

Natural Killer T cells (NKT cells) are a subpopulation of T lymphocytes with unique phenotypic properties and a remarkably broad range of immune effector and regulatory functions. One subset of these cells, known as invariant NKT cells (iNKT cells), has become a significant focus in the search for new and better ways to enhance immunotherapies and vaccination. These unconventional T cells are characterized by their ability to be specifically activated by a range of foreign and self-derived glycolipid antigens presented by CD1d, an MHC class I-related antigen presenting molecule that has evolved to bind and present lipid antigens. The development of synthetic α-galactosylceramides as a family of powerful glycolipid agonists for iNKT cells has led to approaches for augmenting a wide variety of immune responses, including those involved in vaccination against infections and cancers. Here we review the basic background biology of iNKT cells that is relevant to their potential for improving immune responses, and summarize recent work supporting the further development of glycolipid activators of iNKT cells as a new class of vaccine adjuvants.

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

Access this article

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  • Arora P, Venkataswamy MM, Baena A, Bricard G, Li Q, Veerapen N, Ndonye R, Park JJ, Lee JH, Seo KC, Howell AR, Chang YT, Illarionov PA, Besra GS, Chung SK, Porcelli SA (2011) A rapid fluorescence-based assay for classification of iNKT cell activating glycolipids. J Am Chem Soc 133:5198–5201

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Arora P, Baena A, Yu KO, Saini NK, Kharkwal SS, Goldberg MF, Kunnath-Velayudhan S, Carreno LJ, Venkataswamy MM, Kim J, Lazar-Molnar E, Lauvau G, Chang YT, Liu Z, Bittman R, Al-Shamkhani A, Cox LR, Jervis PJ, Veerapen N, Besra GS, Porcelli SA (2014) A single subset of dendritic cells controls the cytokine bias of natural killer T cell responses to diverse glycolipid antigens. Immunity 40:105–116

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Arora P, Kharkwal SS, Ng TW, Kunnath-Velayudhan S, Saini NK, Johndrow CT, Chang YT, Besra GS, Porcelli SA (2015) Endocytic pH regulates cell surface localization of glycolipid antigen loaded CD1d complexes. Chem Phys Lipids 191:75–83

    Article  CAS  PubMed  Google Scholar 

  • Aspeslagh S, Li Y, Yu ED, Pauwels N, Trappeniers M, Girardi E, Decruy T, Van Beneden K, Venken K, Drennan M, Leybaert L, Wang J, Franck RW, Van Calenbergh S, Zajonc DM, Elewaut D (2011) Galactose-modified iNKT cell agonists stabilized by an induced fit of CD1d prevent tumour metastasis. EMBO J 30:2294–2305

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Aspeslagh S, Nemcovic M, Pauwels N, Venken K, Wang J, Van Calenbergh S, Zajonc DM, Elewaut D (2013) Enhanced TCR footprint by a novel glycolipid increases NKT-dependent tumor protection. J Immunol 191:2916–2925

    Article  CAS  PubMed  Google Scholar 

  • Bai L, Sagiv Y, Liu Y, Freigang S, Yu KO, Teyton L, Porcelli SA, Savage PB, Bendelac A (2009) Lysosomal recycling terminates CD1d-mediated presentation of short and polyunsaturated variants of the NKT cell lipid antigen alphaGalCer. Proc Natl Acad Sci U S A 106:10254–10259

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bai L, Constantinides MG, Thomas SY, Reboulet R, Meng F, Koentgen F, Teyton L, Savage PB, Bendelac A (2012) Distinct APCs explain the cytokine bias of alpha-galactosylceramide variants in vivo. J Immunol 188:3053–3061

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Barral P, Polzella P, Bruckbauer A, van Rooijen N, Besra GS, Cerundolo V, Batista FD (2010) CD169(+) macrophages present lipid antigens to mediate early activation of iNKT cells in lymph nodes. Nat Immunol 11:303–312

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bendelac A, Savage PB, Teyton L (2007) The biology of NKT cells. Annu Rev Immunol 25:297–336

    Article  CAS  PubMed  Google Scholar 

  • Benlagha K, Bendelac A (2000) CD1d-restricted mouse V alpha 14 and human V alpha 24 T cells: lymphocytes of innate immunity. Semin Immunol 12:537–542

    Article  CAS  PubMed  Google Scholar 

  • Birkholz AM, Howell AR, Kronenberg M (2015) The alpha and omega of galactosylceramides in T cell immune function. J Biol Chem 290:15365–15370

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Blauvelt ML, Khalili M, Jaung W, Paulsen J, Anderson AC, Brian Wilson S, Howell AR (2008) α-S-GalCer: synthesis and evaluation for iNKT cell stimulation. Bioorg Med Chem Lett 18:6374–6376

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Brennan PJ, Tatituri RV, Brigl M, Kim EY, Tuli A, Sanderson JP, Gadola SD, Hsu FF, Besra GS, Brenner MB (2011) Invariant natural killer T cells recognize lipid self antigen induced by microbial danger signals. Nat Immunol 12:1202–1211

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Brennan PJ, Brigl M, Brenner MB (2013) Invariant natural killer T cells: an innate activation scheme linked to diverse effector functions. Nat Rev Immunol 13:101–117

    Article  CAS  PubMed  Google Scholar 

  • Brennan PJ, Tatituri RV, Heiss C, Watts GF, Hsu FF, Veerapen N, Cox LR, Azadi P, Besra GS, Brenner MB (2014) Activation of iNKT cells by a distinct constituent of the endogenous glucosylceramide fraction. Proc Natl Acad Sci U S A 111:13433–13438

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Brossay L, Jullien D, Cardell S, Sydora BC, Burdin N, Modlin RL, Kronenberg M (1997) Mouse CD1 is mainly expressed on hemopoietic-derived cells. J Immunol 159:1216–1224

    CAS  PubMed  Google Scholar 

  • Burdin N, Brossay L, Degano M, Iijima H, Gui M, Wilson IA, Kronenberg M (2000) Structural requirements for antigen presentation by mouse CD1. Proc Natl Acad Sci U S A 97:10156–10161

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Castano AR, Tangri S, Miller JE, Holcombe HR, Jackson MR, Huse WD, Kronenberg M, Peterson PA (1995) Peptide binding and presentation by mouse CD1. Science 269:223–226

    Article  CAS  PubMed  Google Scholar 

  • Cerundolo V, Salio M (2007) Harnessing NKT cells for therapeutic applications. Curr Top Microbiol Immunol 314:325–340

    CAS  PubMed  Google Scholar 

  • Chang YJ, Huang JR, Tsai YC, Hung JT, Wu D, Fujio M, Wong CH, Yu AL (2007) Potent immune-modulating and anticancer effects of NKT cell stimulatory glycolipids. Proc Natl Acad Sci U S A 104:10299–10304

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chung Y, Qin H, Kang CY, Kim S, Kwak LW, Dong C (2007) An NKT-mediated autologous vaccine generates CD4 T-cell dependent potent antilymphoma immunity. Blood 110:2013–2019

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Corgnac S, Perret R, Derre L, Zhang L, Stirnemann K, Zauderer M, Speiser DE, Mach JP, Romero P, Donda A (2013) CD1d-antibody fusion proteins target iNKT cells to the tumor and trigger long-term therapeutic responses. Cancer Immunol Immunother 62:747–760

    Article  CAS  PubMed  Google Scholar 

  • Corgnac S, Perret R, Zhang L, Mach JP, Romero P, Donda A (2014) iNKT/CD1d-antitumor immunotherapy significantly increases the efficacy of therapeutic CpG/peptide-based cancer vaccine. J Immunother Cancer 2:39

    Article  PubMed  PubMed Central  Google Scholar 

  • Facciotti F, Ramanjaneyulu GS, Lepore M, Sansano S, Cavallari M, Kistowska M, Forss-Petter S, Ni G, Colone A, Singhal A, Berger J, Xia C, Mori L, De Libero G (2012) Peroxisome-derived lipids are self antigens that stimulate invariant natural killer T cells in the thymus. Nat Immunol 13:474–480

    Article  CAS  PubMed  Google Scholar 

  • Faveeuw C, Trottein F (2014) Optimization of natural killer T cell-mediated immunotherapy in cancer using cell-based and nanovector vaccines. Cancer Res 74:1632–1638

    Article  CAS  PubMed  Google Scholar 

  • Forestier C, Takaki T, Molano A, Im JS, Baine I, Jerud ES, Illarionov P, Ndonye R, Howell AR, Santamaria P, Besra GS, Dilorenzo TP, Porcelli SA (2007) Improved outcomes in NOD mice treated with a novel Th2 cytokine-biasing NKT cell activator. J Immunol 178:1415–1425

    Article  CAS  PubMed  Google Scholar 

  • Freigang S, Zadorozhny V, McKinney MK, Krebs P, Herro R, Pawlak J, Kain L, Schrantz N, Masuda K, Liu Y, Savage PB, Bendelac A, Cravatt BF, Teyton L (2010) Fatty acid amide hydrolase shapes NKT cell responses by influencing the serum transport of lipid antigen in mice. J Clin Invest 120:1873–1884

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Freigang S, Landais E, Zadorozhny V, Kain L, Yoshida K, Liu Y, Deng S, Palinski W, Savage PB, Bendelac A, Teyton L (2012) Scavenger receptors target glycolipids for natural killer T cell activation. J Clin Invest 122:3943–3954

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fujii S, Shimizu K, Hemmi H, Fukui M, Bonito AJ, Chen G, Franck RW, Tsuji M, Steinman RM (2006) Glycolipid alpha-C-galactosylceramide is a distinct inducer of dendritic cell function during innate and adaptive immune responses of mice. Proc Natl Acad Sci U S A 103:11252–11257

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fujii S, Shimizu K, Okamoto Y, Kunii N, Nakayama T, Motohashi S, Taniguchi M (2013) NKT cells as an ideal anti-tumor immunotherapeutic. Front Immunol 4:409

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Giaccone G, Punt CJ, Ando Y, Ruijter R, Nishi N, Peters M, von Blomberg BM, Scheper RJ, van der Vliet HJ, van den Eertwegh AJ, Roelvink M, Beijnen J, Zwierzina H, Pinedo HM (2002) A phase I study of the natural killer T-cell ligand alpha-galactosylceramide (KRN7000) in patients with solid tumors. Clin Cancer Res 8:3702–3709

    CAS  PubMed  Google Scholar 

  • Girardi E, Zajonc DM (2012) Molecular basis of lipid antigen presentation by CD1d and recognition by natural killer T cells. Immunol Rev 250:167–179

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Godfrey DI, MacDonald HR, Kronenberg M, Smyth MJ, Van Kaer L (2004) NKT cells: what’s in a name? Nat Rev Immunol 4:231–237

    Article  CAS  PubMed  Google Scholar 

  • Godfrey DI, Pellicci DG, Patel O, Kjer-Nielsen L, McCluskey J, Rossjohn J (2010) Antigen recognition by CD1d-restricted NKT T cell receptors. Semin Immunol 22:61–67

    Article  CAS  PubMed  Google Scholar 

  • Goff RD, Gao Y, Mattner J, Zhou D, Yin N, Cantu C 3rd, Teyton L, Bendelac A, Savage PB (2004) Effects of lipid chain lengths in alpha-galactosylceramides on cytokine release by natural killer T cells. J Am Chem Soc 126:13602–13603

    Article  CAS  PubMed  Google Scholar 

  • Gonzalez-Aseguinolaza G, Van Kaer L, Bergmann CC, Wilson JM, Schmieg J, Kronenberg M, Nakayama T, Taniguchi M, Koezuka Y, Tsuji M (2002) Natural killer T cell ligand alpha-galactosylceramide enhances protective immunity induced by malaria vaccines. J Exp Med 195:617–624

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gumperz JE, Roy C, Makowska A, Lum D, Sugita M, Podrebarac T, Koezuka Y, Porcelli SA, Cardell S, Brenner MB, Behar SM (2000) Murine CD1d-restricted T cell recognition of cellular lipids. Immunity 12:211–221

    Article  CAS  PubMed  Google Scholar 

  • Hermans IF, Silk JD, Gileadi U, Salio M, Mathew B, Ritter G, Schmidt R, Harris AL, Old L, Cerundolo V (2003) 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

    Article  CAS  PubMed  Google Scholar 

  • Hogan AE, O’Reilly V, Dunne MR, Dere RT, Zeng SG, O’Brien C, Amu S, Fallon PG, Exley MA, O’Farrelly C, Zhu X, Doherty DG (2011) Activation of human invariant natural killer T cells with a thioglycoside analogue of alpha-galactosylceramide. Clin Immunol 140:196–207

    Article  CAS  PubMed  Google Scholar 

  • Huang Y, Chen A, Li X, Chen Z, Zhang W, Song Y, Gurner D, Gardiner D, Basu S, Ho DD, Tsuji M (2008) Enhancement of HIV DNA vaccine immunogenicity by the NKT cell ligand, alpha-galactosylceramide. Vaccine 26:1807–1816

    Article  CAS  PubMed  Google Scholar 

  • Huang JR, Tsai YC, Chang YJ, Wu JC, Hung JT, Lin KH, Wong CH, Yu AL (2014) Alpha-galactosylceramide but not phenyl-glycolipids induced NKT cell anergy and IL-33-mediated myeloid-derived suppressor cell accumulation via upregulation of egr2/3. J Immunol 192:1972–1981

    Article  CAS  PubMed  Google Scholar 

  • Hunn MK, Hermans IF (2013) Exploiting invariant NKT cells to promote T-cell responses to cancer vaccines. Oncoimmunology 2:e23789

    Article  PubMed  PubMed Central  Google Scholar 

  • Im JS, Arora P, Bricard G, Molano A, Venkataswamy MM, Baine I, Jerud ES, Goldberg MF, Baena A, Yu KO, Ndonye RM, Howell AR, Yuan W, Cresswell P, Chang YT, Illarionov PA, Besra GS, Porcelli SA (2009) Kinetics and cellular site of glycolipid loading control the outcome of natural killer T cell activation. Immunity 30:888–898

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ishii M, Kojima N (2013) Effective stimulation of invariant natural killer T cells by oligomannose-coated liposomes. Int Immunopharmacol 15:685–692

    Article  CAS  PubMed  Google Scholar 

  • Jervis PJ, Veerapen N, Bricard G, Cox LR, Porcelli SA, Besra GS (2010) Synthesis and biological activity of alpha-glucosyl C24:0 and C20:2 ceramides. Bioorg Med Chem Lett 20:3475–3478

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kain L, Webb B, Anderson BL, Deng S, Holt M, Costanzo A, Zhao M, Self K, Teyton A, Everett C, Kronenberg M, Zajonc DM, Bendelac A, Savage PB, Teyton L (2014) The identification of the endogenous ligands of natural killer T cells reveals the presence of mammalian alpha-linked glycosylceramides. Immunity 41:543–554

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kain L, Costanzo A, Webb B, Holt M, Bendelac A, Savage PB, Teyton L (2015) Endogenous ligands of natural killer T cells are alpha-linked glycosylceramides. Mol Immunol 68:94–97

    Article  CAS  PubMed  Google Scholar 

  • Kamijuku H, Nagata Y, Jiang X, Ichinohe T, Tashiro T, Mori K, Taniguchi M, Hase K, Ohno H, Shimaoka T, Yonehara S, Odagiri T, Tashiro M, Sata T, Hasegawa H, Seino KI (2008) Mechanism of NKT cell activation by intranasal coadministration of alpha-galactosylceramide, which can induce cross-protection against influenza viruses. Mucosal Immunol 1:208–218

    Article  CAS  PubMed  Google Scholar 

  • Kawano T, Cui J, Koezuka Y, Toura I, Kaneko Y, Motoki K, Ueno H, Nakagawa R, Sato H, Kondo E, Koseki H, Taniguchi M (1997) CD1d-restricted and TCR-mediated activation of valpha14 NKT cells by glycosylceramides. Science 278:1626–1629

    Article  CAS  PubMed  Google Scholar 

  • Kim YJ, Ko HJ, Kim YS, Kim DH, Kang S, Kim JM, Chung Y, Kang CY (2008) Alpha-galactosylceramide-loaded, antigen-expressing B cells prime a wide spectrum of antitumor immunity. Int J Cancer 122:2774–2783

    Article  CAS  PubMed  Google Scholar 

  • Kim D, Hung CF, Wu TC, Park YM (2010) DNA vaccine with alpha-galactosylceramide at prime phase enhances anti-tumor immunity after boosting with antigen-expressing dendritic cells. Vaccine 28:7297–7305

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • King IL, Amiel E, Tighe M, Mohrs K, Veerapen N, Besra G, Mohrs M, Leadbetter EA (2013) The mechanism of splenic invariant NKT cell activation dictates localization in vivo. J Immunol 191:572–582

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ko SY, Ko HJ, Chang WS, Park SH, Kweon MN, Kang CY (2005) Alpha-galactosylceramide can act as a nasal vaccine adjuvant inducing protective immune responses against viral infection and tumor. J Immunol 175:3309–3317

    Article  CAS  PubMed  Google Scholar 

  • Kobayashi E, Motoki K, Uchida T, Fukushima H, Koezuka Y (1995) KRN7000, a novel immunomodulator, and its antitumor activities. Oncol Res 7:529–534

    CAS  PubMed  Google Scholar 

  • Kopecky-Bromberg SA, Fraser KA, Pica N, Carnero E, Moran TM, Franck RW, Tsuji M, Palese P (2009) Alpha-C-galactosylceramide as an adjuvant for a live attenuated influenza virus vaccine. Vaccine 27:3766–3774

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kunii N, Horiguchi S, Motohashi S, Yamamoto H, Ueno N, Yamamoto S, Sakurai D, Taniguchi M, Nakayama T, Okamoto Y (2009) Combination therapy of in vitro-expanded natural killer T cells and alpha-galactosylceramide-pulsed antigen-presenting cells in patients with recurrent head and neck carcinoma. Cancer Sci 100:1092–1098

    Article  CAS  PubMed  Google Scholar 

  • Laurent X, Bertin B, Renault N, Farce A, Speca S, Milhomme O, Millet R, Desreumaux P, Henon E, Chavatte P (2014a) Switching invariant natural killer T (iNKT) cell response from anticancerous to anti-inflammatory effect: molecular bases. J Med Chem 57:5489–5508

    Article  CAS  PubMed  Google Scholar 

  • Laurent X, Renault N, Farce A, Chavatte P, Henon E (2014b) Relationships between Th1 or Th2 iNKT cell activity and structures of CD1d-antigen complexes: meta-analysis of CD1d-glycolipids dynamics simulations. PLoS Comput Biol 10:e1003902

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Lawton AP, Prigozy TI, Brossay L, Pei B, Khurana A, Martin D, Zhu T, Spate K, Ozga M, Honing S, Bakke O, Kronenberg M (2005) The mouse CD1d cytoplasmic tail mediates CD1d trafficking and antigen presentation by adaptor protein 3-dependent and -independent mechanisms. J Immunol 174:3179–3186

    Article  CAS  PubMed  Google Scholar 

  • Lee A, Farrand KJ, Dickgreber N, Hayman CM, Jurs S, Hermans IF, Painter GF (2006) Novel synthesis of alpha-galactosyl-ceramides and confirmation of their powerful NKT cell agonist activity. Carbohydr Res 341:2785–2798

    Article  CAS  PubMed  Google Scholar 

  • Lee YS, Lee KA, Lee JY, Kang MH, Song YC, Baek DJ, Kim S, Kang CY (2011) An alpha-GalCer analogue with branched acyl chain enhances protective immune responses in a nasal influenza vaccine. Vaccine 29:417–425

    Article  CAS  PubMed  Google Scholar 

  • Leung B, Harris HW (2010) NKT cells in sepsis. Clin Dev Immunol 2010

  • Li Q, Ndonye RM, Illarionov PA, Yu KO, Jerud ES, Diaz K, Bricard G, Porcelli SA, Besra GS, Chang YT, Howell AR (2007) Rapid identification of immunostimulatory alpha-galactosylceramides using synthetic combinatorial libraries. J Comb Chem 9:1084–1093

    Article  CAS  PubMed  Google Scholar 

  • Li X, Chen G, Garcia-Navarro R, Franck RW, Tsuji M (2009) Identification of C-glycoside analogues that display a potent biological activity against murine and human invariant natural killer T cells. Immunology 127:216–225

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Li X, Fujio M, Imamura M, Wu D, Vasan S, Wong CH, Ho DD, Tsuji M (2010) Design of a potent CD1d-binding NKT cell ligand as a vaccine adjuvant. Proc Natl Acad Sci U S A 107:13010–13015

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Li X, Kawamura A, Andrews CD, Miller JL, Wu D, Tsao T, Zhang M, Oren D, Padte NN, Porcelli SA, Wong CH, Kappe SH, Ho DD, Tsuji M (2015) Colocalization of a CD1d-binding glycolipid with a radiation-attenuated Sporozoite vaccine in lymph node-resident dendritic cells for a robust adjuvant effect. J Immunol 195:2710–2721

    Article  CAS  PubMed  Google Scholar 

  • Macho-Fernandez E, Cruz LJ, Ghinnagow R, Fontaine J, Bialecki E, Frisch B, Trottein F, Faveeuw C (2014) Targeted delivery of alpha-galactosylceramide to CD8alpha + dendritic cells optimizes type I NKT cell-based antitumor responses. J Immunol 193:961–969

    Article  CAS  PubMed  Google Scholar 

  • Marrero I, Ware R, Kumar V (2015) Type II NKT cells in inflammation, autoimmunity, microbial immunity, and cancer. Front Immunol 6:316

    Article  PubMed  PubMed Central  CAS  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Morita M, Motoki K, Akimoto K, Natori T, Sakai T, Sawa E, Yamaji K, Koezuka Y, Kobayashi E, Fukushima H (1995) Structure-activity relationship of alpha-galactosylceramides against B16-bearing mice. J Med Chem 38:2176–2187

    Article  CAS  PubMed  Google Scholar 

  • Motohashi S, Okamoto Y, Yoshino I, Nakayama T (2011) Anti-tumor immune responses induced by iNKT cell-based immunotherapy for lung cancer and head and neck cancer. Clin Immunol 140:167–176

    Article  CAS  PubMed  Google Scholar 

  • Nakamura T, Yamazaki D, Yamauchi J, Harashima H (2013) The nanoparticulation by octaarginine-modified liposome improves alpha-galactosylceramide-mediated antitumor therapy via systemic administration. J Control Release 171:216–224

    Article  CAS  PubMed  Google Scholar 

  • Nieda M, Okai M, Tazbirkova A, Lin H, Yamaura A, Ide K, Abraham R, Juji T, Macfarlane DJ, Nicol AJ (2004) Therapeutic activation of Valpha24 + Vbeta11+ NKT cells in human subjects results in highly coordinated secondary activation of acquired and innate immunity. Blood 103:383–389

    Article  CAS  PubMed  Google Scholar 

  • Okai M, Nieda M, Tazbirkova A, Horley D, Kikuchi A, Durrant S, Takahashi T, Boyd A, Abraham R, Yagita H, Juji T, Nicol A (2002) Human peripheral blood Valpha24+ Vbeta11+ NKT cells expand following administration of alpha-galactosylceramide-pulsed dendritic cells. Vox Sang 83:250–253

    Article  CAS  PubMed  Google Scholar 

  • Okamoto Y, Fujikawa A, Kurosaki M, Yamasaki K, Sakurai D, Horiguchi S, Nakayama T (2011) Nasal submucosal administration of antigen-presenting cells induces effective immunological responses in cancer immunotherapy. Adv Otorhinolaryngol 72:149–152

    PubMed  Google Scholar 

  • Padte NN, Li X, Tsuji M, Vasan S (2011) Clinical development of a novel CD1d-binding NKT cell ligand as a vaccine adjuvant. Clin Immunol 140:142–151

    Article  CAS  PubMed  Google Scholar 

  • Padte NN, Boente-Carrera M, Andrews CD, McManus J, Grasperge BF, Gettie A, Coelho-dos-Reis JG, Li X, Wu D, Bruder JT, Sedegah M, Patterson N, Richie TL, Wong CH, Ho DD, Vasan S, Tsuji M (2013) A glycolipid adjuvant, 7DW8-5, enhances CD8+ T cell responses induced by an adenovirus-vectored malaria vaccine in non-human primates. PLoS One 8:e78407

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Parekh VV, Singh AK, Wilson MT, Olivares-Villagomez D, Bezbradica JS, Inazawa H, Ehara H, Sakai T, Serizawa I, Wu L, Wang CR, Joyce S, Van Kaer L (2004) Quantitative and qualitative differences in the in vivo response of NKT cells to distinct alpha- and beta-anomeric glycolipids. J Immunol 173:3693–3706

    Article  CAS  PubMed  Google Scholar 

  • Parekh VV, Wilson MT, Olivares-Villagomez D, Singh AK, Wu L, Wang CR, Joyce S, Van Kaer L (2005) Glycolipid antigen induces long-term natural killer T cell anergy in mice. J Clin Invest 115:2572–2583

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Patel O, Pellicci DG, Gras S, Sandoval-Romero ML, Uldrich AP, Mallevaey T, Clarke AJ, Le Nours J, Theodossis A, Cardell SL, Gapin L, Godfrey DI, Rossjohn J (2012) Recognition of CD1d-sulfatide mediated by a type II natural killer T cell antigen receptor. Nat Immunol 13:857–863

    Article  CAS  PubMed  Google Scholar 

  • Pellicci DG, Hammond KJ, Uldrich AP, Baxter AG, Smyth MJ, Godfrey DI (2002) A natural killer T (NKT) cell developmental pathway iInvolving a thymus-dependent NK1.1(−)CD4(+) CD1d-dependent precursor stage. J Exp Med 195:835–844

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pellicci DG, Patel O, Kjer-Nielsen L, Pang SS, Sullivan LC, Kyparissoudis K, Brooks AG, Reid HH, Gras S, Lucet IS, Koh R, Smyth MJ, Mallevaey T, Matsuda JL, Gapin L, McCluskey J, Godfrey DI, Rossjohn J (2009) Differential recognition of CD1d-alpha-galactosyl ceramide by the V beta 8.2 and V beta 7 semi-invariant NKT T cell receptors. Immunity 31:47–59

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pellicci DG, Clarke AJ, Patel O, Mallevaey T, Beddoe T, Le Nours J, Uldrich AP, McCluskey J, Besra GS, Porcelli SA, Gapin L, Godfrey DI, Rossjohn J (2011) Recognition of beta-linked self glycolipids mediated by natural killer T cell antigen receptors. Nat Immunol 12:827–833

    Article  CAS  PubMed  Google Scholar 

  • Router AP, Lindhorst TK, Boons GJ, Witczak ZJ (2010) Carbohydrate chemistry: chemical and biological approaches. Royal Society of Chemistry, Cambridge

    Book  Google Scholar 

  • Richter J, Neparidze N, Zhang L, Nair S, Monesmith T, Sundaram R, Miesowicz F, Dhodapkar KM, Dhodapkar MV (2013) Clinical regressions and broad immune activation following combination therapy targeting human NKT cells in myeloma. Blood 121:423–430

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rossjohn J, Pellicci DG, Patel O, Gapin L, Godfrey DI (2012) Recognition of CD1d-restricted antigens by natural killer T cells. Nat Rev Immunol 12:845–857

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Salio M, Silk JD, Jones EY, Cerundolo V (2014) Biology of CD1- and MR1-restricted T cells. Annu Rev Immunol 32:323–366

    Article  CAS  PubMed  Google Scholar 

  • Schmieg J, Yang G, Franck RW, Tsuji M (2003) Superior protection against malaria and melanoma metastases by a C-glycoside analogue of the natural killer T cell ligand [alpha]-galactosylceramide. J Exp Med 198:1631–1641

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shibolet O, Alper R, Zlotogarov L, Thalenfeld B, Engelhardt D, Rabbani E, Ilan Y (2003) NKT and CD8 lymphocytes mediate suppression of hepatocellular carcinoma growth via tumor antigen-pulsed dendritic cells. Int J Cancer 106:236–243

    Article  CAS  PubMed  Google Scholar 

  • Silk JD, Hermans IF, Gileadi U, Chong TW, Shepherd D, Salio M, Mathew B, Schmidt RR, Lunt SJ, Williams KJ, Stratford IJ, Harris AL, Cerundolo V (2004) Utilizing the adjuvant properties of CD1d-dependent NK T cells in T cell-mediated immunotherapy. J Clin Invest 114:1800–1811

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Singh M, Quispe-Tintaya W, Chandra D, Jahangir A, Venkataswamy MM, Ng TW, Sharma-Kharkwal S, Carreno LJ, Porcelli SA, Gravekamp C (2014) Direct incorporation of the NKT-cell activator alpha-galactosylceramide into a recombinant Listeria monocytogenes improves breast cancer vaccine efficacy. Br J Cancer 111:1945–1954

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Stirnemann K, Romero JF, Baldi L, Robert B, Cesson V, Besra GS, Zauderer M, Wurm F, Corradin G, Mach JP, Macdonald HR, Donda A (2008) Sustained activation and tumor targeting of NKT cells using a CD1d-anti-HER2-scFv fusion protein induce antitumor effects in mice. J Clin Invest 118:994–1005

    CAS  PubMed  PubMed Central  Google Scholar 

  • Sullivan BA, Kronenberg M (2005) Activation or anergy: NKT cells are stunned by alpha-galactosylceramide. J Clin Invest 115:2328–2329

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sullivan BA, Nagarajan NA, Wingender G, Wang J, Scott I, Tsuji M, Franck RW, Porcelli SA, Zajonc DM, Kronenberg M (2010) Mechanisms for glycolipid antigen-driven cytokine polarization by Valpha14i NKT cells. J Immunol 184:141–153

    Article  CAS  PubMed  Google Scholar 

  • Tashiro T, Hongo N, Nakagawa R, K-i S, Watarai H, Ishii Y, Taniguchi M, Mori K (2008) RCAI-17, 22, 24–26, 29, 31, 34–36, 38–40, and 88, the analogs of KRN7000 with a sulfonamide linkage: their synthesis and bioactivity for mouse natural killer T cells to produce Th2-biased cytokines. Bioorg Med Chem 16:8896–8906

    Article  CAS  PubMed  Google Scholar 

  • Teng MW, Westwood JA, Darcy PK, Sharkey J, Tsuji M, Franck RW, Porcelli SA, Besra GS, Takeda K, Yagita H, Kershaw MH, Smyth MJ (2007) Combined natural killer T-cell based immunotherapy eradicates established tumors in mice. Cancer Res 67:7495–7504

    Article  CAS  PubMed  Google Scholar 

  • Thapa P, Zhang G, Xia C, Gelbard A, Overwijk WW, Liu C, Hwu P, Chang DZ, Courtney A, Sastry JK, Wang PG, Li C, Zhou D (2009) Nanoparticle formulated alpha-galactosylceramide activates NKT cells without inducing anergy. Vaccine 27:3484–3488

    Article  CAS  PubMed  Google Scholar 

  • Uldrich AP, Crowe NY, Kyparissoudis K, Pellicci DG, Zhan Y, Lew AM, Bouillet P, Strasser A, Smyth MJ, Godfrey DI (2005) NKT cell stimulation with glycolipid antigen in vivo: costimulation-dependent expansion, Bim-dependent contraction, and hyporesponsiveness to further antigenic challenge. J Immunol 175:3092–3101

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • van den Elzen P, Garg S, Leon L, Brigl M, Leadbetter EA, Gumperz JE, Dascher CC, Cheng TY, Sacks FM, Illarionov PA, Besra GS, Kent SC, Moody DB, Brenner MB (2005) Apolipoprotein-mediated pathways of lipid antigen presentation. Nature 437:906–910

    Article  PubMed  CAS  Google Scholar 

  • Van Rhijn I, Godfrey DI, Rossjohn J, Moody DB (2015) Lipid and small-molecule display by CD1 and MR1. Nat Rev Immunol 15:643–654

    Article  CAS  PubMed  Google Scholar 

  • Veerapen N, Reddington F, Bricard G, Porcelli SA, Besra GS (2010) Synthesis and biological activity of alpha-L-fucosyl ceramides, analogues of the potent agonist, alpha-D-galactosyl ceramide KRN7000. Bioorg Med Chem Lett 20:3223–3226

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Veldt BJ, van der Vliet HJ, von Blomberg BM, van Vlierberghe H, Gerken G, Nishi N, Hayashi K, Scheper RJ, de Knegt RJ, van den Eertwegh AJ, Janssen HL, van Nieuwkerk CM (2007) Randomized placebo controlled phase I/II trial of alpha-galactosylceramide for the treatment of chronic hepatitis C. J Hepatol 47:356–365

    Article  CAS  PubMed  Google Scholar 

  • Venkataswamy MM, Porcelli SA (2010) Lipid and glycolipid antigens of CD1d-restricted natural killer T cells. Semin Immunol 22:68–78

    Article  CAS  PubMed  Google Scholar 

  • Venkataswamy MM, Baena A, Goldberg MF, Bricard G, Im JS, Chan J, Reddington F, Besra GS, Jacobs WR Jr, Porcelli SA (2009) Incorporation of NKT cell-activating glycolipids enhances immunogenicity and vaccine efficacy of Mycobacterium Bovis Bacillus Calmette-Guerin. J Immunol 183:1644–1656

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Venkataswamy MM, Ng TW, Kharkwal SS, Carreno LJ, Johnson AJ, Kunnath-Velayudhan S, Liu Z, Bittman R, Jervis PJ, Cox LR, Besra GS, Wen X, Yuan W, Tsuji M, Li X, Ho DD, Chan J, Lee S, Frothingham R, Haynes BF, Panas MW, Gillard GO, Sixsmith JD, Korioth-Schmitz B, Schmitz JE, Larsen MH, Jacobs WR Jr, Porcelli SA (2014) Improving Mycobacterium Bovis Bacillus Calmette-Guerin as a vaccine delivery vector for viral antigens by incorporation of glycolipid activators of NKT cells. PLoS One 9:e108383

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Woltman AM, Ter Borg MJ, Binda RS, Sprengers D, von Blomberg BM, Scheper RJ, Hayashi K, Nishi N, Boonstra A, van der Molen R, Janssen HL (2009) Alpha-galactosylceramide in chronic hepatitis B infection: results from a randomized placebo-controlled phase I/II trial. Antivir Ther 14:809–818

    Article  CAS  PubMed  Google Scholar 

  • Wun KS, Cameron G, Patel O, Pang SS, Pellicci DG, Sullivan LC, Keshipeddy S, Young MH, Uldrich AP, Thakur MS, Richardson SK, Howell AR, Illarionov PA, Brooks AG, Besra GS, McCluskey J, Gapin L, Porcelli SA, Godfrey DI, Rossjohn J (2011) A molecular basis for the exquisite CD1d-restricted antigen specificity and functional responses of natural killer T cells. Immunity 34:327–339

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wun KS, Ross F, Patel O, Besra GS, Porcelli SA, Richardson SK, Keshipeddy S, Howell AR, Godfrey DI, Rossjohn J (2012) Human and mouse type I natural killer T cell antigen receptors exhibit different fine specificities for CD1d-antigen complex. J Biol Chem 287:39139–39148

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yamasaki K, Horiguchi S, Kurosaki M, Kunii N, Nagato K, Hanaoka H, Shimizu N, Ueno N, Yamamoto S, Taniguchi M, Motohashi S, Nakayama T, Okamoto Y (2011) Induction of NKT cell-specific immune responses in cancer tissues after NKT cell-targeted adoptive immunotherapy. Clin Immunol 138:255–265

    Article  CAS  PubMed  Google Scholar 

  • Youn HJ, Ko SY, Lee KA, Ko HJ, Lee YS, Fujihashi K, Boyaka PN, Kim SH, Horimoto T, Kweon MN, Kang CY (2007) A single intranasal immunization with inactivated influenza virus and alpha-galactosylceramide induces long-term protective immunity without redirecting antigen to the central nervous system. Vaccine 25:5189–5198

    Article  CAS  PubMed  Google Scholar 

  • Yu KO, Porcelli SA (2005) The diverse functions of CD1d-restricted NKT cells and their potential for immunotherapy. Immunol Lett 100:42–55

    Article  CAS  PubMed  Google Scholar 

  • Yu KO, Im JS, Molano A, Dutronc Y, Illarionov PA, Forestier C, Fujiwara N, Arias I, Miyake S, Yamamura T, Chang YT, Besra GS, Porcelli SA (2005) Modulation of CD1d-restricted NKT cell responses by using N-acyl variants of [alpha]-galactosylceramides. Proc Natl Acad Sci U S A 102:3383–3388

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yuan W, Qi X, Tsang P, Kang SJ, Illarionov PA, Besra GS, Gumperz J, Cresswell P (2007) Saposin B is the dominant saposin that facilitates lipid binding to human CD1d molecules. Proc Natl Acad Sci U S A 104:5551–5556

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhou D, Cantu C 3rd, Sagiv Y, Schrantz N, Kulkarni AB, Qi X, Mahuran DJ, Morales CR, Grabowski GA, Benlagha K, Savage P, Bendelac A, Teyton L (2004a) Editing of CD1d-bound lipid antigens by endosomal lipid transfer proteins. Science 303:523–527

    Article  CAS  PubMed  Google Scholar 

  • Zhou D, Mattner J, Cantu C 3rd, Schrantz N, Yin N, Gao Y, Sagiv Y, Hudspeth K, Wu YP, Yamashita T, Teneberg S, Wang D, Proia RL, Levery SB, Savage PB, Teyton L, Bendelac A (2004b) Lysosomal glycosphingolipid recognition by NKT cells. Science 306:1786–1789

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The authors were supported by grants from NIH/NIAID (RO1 AI45889, RO1 AI093649 and PO1 AI063537).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Steven A. Porcelli.

Ethics declarations

Financial disclosure

S. Porcelli is a paid consultant for Vaccinex, Inc., which has commercial interest in the area of iNKT cell based therapeutics and vaccines. The other authors declare the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Additional information

Shalu Sharma Kharkwal and Pooja Arora contributed equally to this work.

This article is published in the Special Issue CD1, MR1, NKT, and MAIT: Evolution and Origins of Non-peptidic Antigen Recognition by T lymphocytes with Guest Editor Dr. Dirk Zajonc.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kharkwal, S.S., Arora, P. & Porcelli, S.A. Glycolipid activators of invariant NKT cells as vaccine adjuvants. Immunogenetics 68, 597–610 (2016). https://doi.org/10.1007/s00251-016-0925-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00251-016-0925-y

Keywords

Navigation