Boosting the immune response: the use of iNKT cell ligands as vaccine adjuvants

Abstract

Natural killer T (NKT) cells comprise a small, but important T cell subset and are thought to bridge the innate and adaptive immune responses. The discovery of NKT cells and extensive research on their activating ligands have paved the way for modulation of these potent immunoregulatory cells in order to improve the outcome of various clinical conditions. Efforts to modulate NKT cell effector functions have ranged from therapy for influenza to anti-tumor immunotherapy. These approaches have also led to the use of NKT cell agonists such as α-Galactosylceramide (α-GalCer) and its analogs as vaccine adjuvants, an approach that is aimed at boosting specific B and T cell responses to a vaccine candidate by concomitant activation of NKT cells. In this review we will provide a comprehensive overview of the efforts made in using α-GalCer and its analogs as vaccine adjuvants. The diverse array of vaccination strategies used, as well as the role of NKT cell activating adjuvants will be discussed, with focus on vaccines against malaria, HIV, influenza and tumor vaccines. Collectively, these studies demonstrate the efficacy of NKT cell-specific agonists as adjuvants and suggest that these compounds warrant serious consideration during the development of vaccination strategies.

Keywords

vaccines / NKT cells and CD1d

References

[1] Bauer C, Dauer M, Saraj S, Schnurr M, Bauernfeind F, Sterzik A, Junkmann J, Jakl V, Kiefl R, Oduncu F, Emmerich B, Mayr D, Mussack T, Bruns C, Rüttinger D, Conrad C, Jauch K W, Endres S, Eigler A (2011). Dendritic cell-based vaccination of patients with advanced pancreatic carcinoma: results of a pilot study. Cancer Immunol Immunother, 60(8): 1097–1107

[2] Blauvelt M L, Khalili M, Jaung W, Paulsen J, Anderson A C, Brian Wilson S, Howell A R (2008). Alpha-S-GalCer: synthesis and evaluation for iNKT cell stimulation. Bioorg Med Chem Lett, 18(24): 6374–6376

[3] Burdin N, Brossay L, Koezuka Y, Smiley S T, Grusby M J, Gui M, Taniguchi M, Hayakawa K, Kronenberg M (1998). Selective ability of mouse CD1 to present glycolipids: alpha-galactosylceramide specifically stimulates V alpha 14⁺ NK T lymphocytes. J Immunol, 161(7): 3271–3281

[4] Carnaud C, Lee D, Donnars O, Park S H, Beavis A, Koezuka Y, Bendelac A (1999). Cutting edge: Cross-talk between cells of the innate immune system: NKT cells rapidly activate NK cells. J Immunol, 163(9): 4647–4650

[5] Chung Y, Qin H, Kang C Y, Kim S, Kwak L W, Dong C (2007). An NKT-mediated autologous vaccine generates CD4 T-cell dependent potent antilymphoma immunity. Blood, 110(6): 2013–2019

[6] Clyde D F (1975). Immunization of man against falciparum and vivax malaria by use of attenuated sporozoites. Am J Trop Med Hyg, 24(3): 397–401

[7] Courtney A N, Thapa P, Singh S, Wishahy A M, Zhou D, Sastry K J (2011). Intranasal but not intravenous delivery of the adjuvant alpha-galactosylceramide permits repeated stimulation of natural killer T cells in the lung. Eur J Immunol, 41(11):3312–3322

[8] Crowe N Y, Coquet J M, Berzins S P, Kyparissoudis K, Keating R, Pellicci D G, Hayakawa Y, Godfrey D I, Smyth M J (2005). Differential antitumor immunity mediated by NKT cell subsets in vivo. J Exp Med, 202(9): 1279–1288

[9] Fleuridor R, Wilson B, Hou R, Landay A, Kessler H, Al-Harthi L (2003). CD1d-restricted natural killer T cells are potent targets for human immunodeficiency virus infection. Immunology, 108(1): 3–9

[10] Fowlkes B J, Kruisbeek A M, Ton-That H, Weston M A, Coligan J E, Schwartz R H, Pardoll D M (1987). A novel population of T-cell receptor alpha beta-bearing thymocytes which predominantly expresses a single V beta gene family. Nature, 329(6136): 251–254

[11] Giaccone G, Punt C J, Ando Y, Ruijter R, Nishi N, Peters M, von Blomberg B M, Scheper R J, van der Vliet H J, van den Eertwegh A J, Roelvink M, Beijnen J, Zwierzina H, Pinedo H M (2002). A phase I study of the natural killer T-cell ligand alpha-galactosylceramide (KRN7000) in patients with solid tumors. Clin Cancer Res, 8(12): 3702–3709

[12] Gonzalez-Aseguinolaza G, Van Kaer L, Bergmann C C, Wilson J M, 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(5): 617–624

[13] Hogan A E, O’Reilly V, Dunne M R, Dere R T, Zeng S G, O’Brien C, Amu S, Fallon P G, Exley M A, O’Farrelly C, Zhu X, Doherty D G (2011). Activation of human invariant natural killer T cells with a thioglycoside analogue of α-galactosylceramide. Clin Immunol, 140(2): 196–207

[14] Huang Y, Chen A, Li X, Chen Z, Zhang W, Song Y, Gurner D, Gardiner D, Basu S, Ho D D, Tsuji M (2008). Enhancement of HIV DNA vaccine immunogenicity by the NKT cell ligand, alpha-galactosylceramide. Vaccine, 26(15): 1807–1816

[15] Joyce S, Woods A S, Yewdell J W, Bennink J R, De Silva A D, Boesteanu A, Balk S P, Cotter R J, Brutkiewicz R R (1998). Natural ligand of mouse CD1d1: cellular glycosylphosphatidylinositol. Science, 279(5356): 1541–1544

[16] 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 K I (2008). Mechanism of NKT cell activation by intranasal coadministration of alpha-galactosylceramide, which can induce cross-protection against influenza viruses. Mucosal Immunol, 1(3): 208–218

[17] Kawakami K, Kinjo Y, Yara S, Koguchi Y, Uezu K, Nakayama T, Taniguchi M, Saito A (2001). Activation of Valpha14(+) natural killer T cells by alpha-galactosylceramide results in development of Th1 response and local host resistance in mice infected with Cryptococcus neoformans. Infect Immun, 69(1): 213–220

[18] Kawano T, Cui J, Koezuka Y, Toura I, Kaneko Y, Motoki K, Ueno H, Nakagawa R, Sato H, Kondo E, Koseki H, Taniguchi M (1997). CD1d-restricted and TCR-mediated activation of valpha14 NKT cells by glycosylceramides. Science, 278(5343): 1626–1629

[19] Kim D, Hung C F, Wu T C, Park Y M (2010). DNA vaccine with α-galactosylceramide at prime phase enhances anti-tumor immunity after boosting with antigen-expressing dendritic cells. Vaccine, 28(45): 7297–7305

[20] Kim Y J, Ko H J, Kim Y S, Kim D H, Kang S, Kim J M, Chung Y, Kang C Y (2008). Alpha-Galactosylceramide-loaded, antigen-expressing B cells prime a wide spectrum of antitumor immunity. Int J Cancer, 122(12): 2774–2783

[21] Kinjo Y, Tupin E, Wu D, Fujio M, Garcia-Navarro R, Benhnia M R, Zajonc D M, Ben-Menachem G, Ainge G D, Painter G F, Khurana A, Hoebe K, Behar S M, Beutler B, Wilson I A, Tsuji M, Sellati T J, Wong C H, Kronenberg M (2006). Natural killer T cells recognize diacylglycerol antigens from pathogenic bacteria. Nat Immunol, 7(9): 978–986

[22] Kinjo Y, Wu D, Kim G, Xing G W, Poles M A, Ho D D, Tsuji M, Kawahara K, Wong C H, Kronenberg M (2005). Recognition of bacterial glycosphingolipids by natural killer T cells. Nature, 434(7032): 520–525

[23] Ko H J, Lee J M, Kim Y J, Kim Y S, Lee K A, Kang C Y (2009). Immunosuppressive myeloid-derived suppressor cells can be converted into immunogenic APCs with the help of activated NKT cells: an alternative cell-based antitumor vaccine. J Immunol, 182(4): 1818–1828

[24] Ko S Y, Ko H J, Chang W S, Park S H, Kweon M N, Kang C Y (2005). alpha-Galactosylceramide can act as a nasal vaccine adjuvant inducing protective immune responses against viral infection and tumor. J Immunol, 175(5): 3309–3317

[25] Kobayashi E, Motoki K, Uchida T, Fukushima H, Koezuka Y (1995). KRN7000, a novel immunomodulator, and its antitumor activities. Oncol Res, 7(10–11): 529–534

[26] Kopecky-Bromberg S A, Fraser K A, Pica N, Carnero E, Moran T M, Franck R W, Tsuji M, Palese P (2009). Alpha-C-galactosylceramide as an adjuvant for a live attenuated influenza virus vaccine. Vaccine, 27(28): 3766–3774

[27] Koseki H, Asano H, Inaba T, Miyashita N, Moriwaki K, Lindahl K F, Mizutani Y, Imai K, Taniguchi M (1991). Dominant expression of a distinctive V14⁺ T-cell antigen receptor alpha chain in mice. Proc Natl Acad Sci USA, 88(17): 7518–7522

[28] Lee P T, Benlagha K, Teyton L, Bendelac A (2002). Distinct functional lineages of human V(alpha)24 natural killer T cells. J Exp Med, 195(5): 637–641

[29] Lee Y S, Lee K A, Lee J Y, Kang M H, Song Y C, Baek D J, Kim S, Kang C Y (2011). An α-GalCer analogue with branched acyl chain enhances protective immune responses in a nasal influenza vaccine. Vaccine, 29(3): 417–425

[30] Li X, Fujio M, Imamura M, Wu D, Vasan S, Wong C H, Ho D D, Tsuji M (2010a). Design of a potent CD1d-binding NKT cell ligand as a vaccine adjuvant. Proc Natl Acad Sci USA, 107(29): 13010–13015

[31] Li Y, Girardi E, Wang J, Yu E D, Painter G F, Kronenberg M, Zajonc D M (2010b). The Vα14 invariant natural killer T cell TCR forces microbial glycolipids and CD1d into a conserved binding mode. J Exp Med, 207(11): 2383–2393

[32] Lu X, Song L, Metelitsa L S, Bittman R (2006). Synthesis and evaluation of an alpha-C-galactosylceramide analogue that induces Th1-biased responses in human natural killer T cells. ChemBioChem, 7(11): 1750–1756

[33] Makino Y, Kanno R, Ito T, Higashino K, Taniguchi M (1995). Predominant expression of invariant V alpha 14+ TCR alpha chain in NK1.1⁺ T cell populations. Int Immunol, 7(7): 1157–1161

[34] Matangkasombut P, Pichavant M, Yasumi T, Hendricks C, Savage P B, Dekruyff R H, Umetsu D T (2008). Direct activation of natural killer T cells induces airway hyperreactivity in nonhuman primates. J Allergy Clin Immunol, 121(5): 1287–1289

[35] Mattner J, Debord K L, Ismail N, Goff R D, Cantu C 3rd, Zhou D, Saint-Mezard P, Wang V, Gao Y, Yin N, Hoebe K, Schneewind O, Walker D, Beutler B, Teyton L, Savage P B, Bendelac A (2005). Exogenous and endogenous glycolipid antigens activate NKT cells during microbial infections. Nature, 434(7032): 525–529

[36] Miyamoto K, Miyake S, Yamamura T (2001). A synthetic glycolipid prevents autoimmune encephalomyelitis by inducing TH2 bias of natural killer T cells. Nature, 413(6855): 531–534

[37] Molling J W, Kölgen W, van der Vliet H J, Boomsma M F, Kruizenga H, Smorenburg C H, Molenkamp B G, Langendijk J A, Leemans C R, von Blomberg B M, Scheper R J, van den Eertwegh A J (2005). Peripheral blood IFN-gamma-secreting Valpha24⁺ Vbeta11⁺ NKT cell numbers are decreased in cancer patients independent of tumor type or tumor load. Int J Cancer, 116(1): 87–93

[38] Motsinger A, Haas D W, Stanic A K, Van Kaer L, Joyce S, Unutmaz D (2002). CD1d-restricted human natural killer T cells are highly susceptible to human immunodeficiency virus 1 infection. J Exp Med, 195(7): 869–879

[39] Nakagawa R, Serizawa I, Motoki K, Sato M, Ueno H, Iijima R, Nakamura H, Shimosaka A, Koezuka Y (2000). Antitumor activity of alpha-galactosylceramide, KRN7000, in mice with the melanoma B16 hepatic metastasis and immunohistological study of tumor infiltrating cells. Oncol Res, 12(2): 51–58

[40] Nam J H, Kim E H, Song D, Choi Y K, Kim J K, Poo H (2011). Emergence of mammalian species-infectious and-pathogenic avian influenza H6N5 virus with no evidence of adaptation. J Virol, 7(23):3281–3286

[41] Natori T, Akimoto K, Motoki K, Koezuka Y, Higa T (1997). Development of KRN7000, derived from agelasphin produced by okinawan sponge. Nihon Yakurigaku Zasshi, 110 Suppl 163P–68P

[42] Niemeyer M, Darmoise A, Mollenkopf H J, Hahnke K, Hurwitz R, Besra G S, Schaible U E, Kaufmann S H (2008). Natural killer T-cell characterization through gene expression profiling: an account of versatility bridging T helper type 1 (Th1), Th2 and Th17 immune responses. Immunology, 123(1): 45–56

[43] Osada T, Morse M A, Lyerly H K, Clay T M (2005). Ex vivo expanded human CD4⁺ regulatory NKT cells suppress expansion of tumor antigen-specific CTLs. Int Immunol, 17(9): 1143–1155

[44] Parekh V V, Wilson M T, Olivares-Villagómez D, Singh A K, Wu L, Wang C R, Joyce S, Van Kaer L (2005). Glycolipid antigen induces long-term natural killer T cell anergy in mice. J Clin Invest, 115(9): 2572–2583

[45] Petersen T R, Sika-Paotonu D, Knight D A, Dickgreber N, Farrand K J, Ronchese F, Hermans I F (2010). Potent anti-tumor responses to immunization with dendritic cells loaded with tumor tissue and an NKT cell ligand. Immunol Cell Biol, 88(5): 596–604

[46] Porcelli S, Gerdes D, Fertig A M, Balk S P (1996). Human T cells expressing an invariant V alpha 24-J alpha Q TCR alpha are CD4- and heterogeneous with respect to TCR beta expression. Hum Immunol, 48(1–2): 63–67

[47] Roberts T J, Sriram V, Spence P M, Gui M, Hayakawa K, Bacik I, Bennink J R, Yewdell J W, Brutkiewicz R R (2002). Recycling CD1d1 molecules present endogenous antigens processed in an endocytic compartment to NKT cells. J Immunol, 168(11): 5409–5414

[48] Rui-Hua Z, Hong-Yu C, Ming-Ju X, Kai L, Hua-Lan C, Cun-Lian W, Dong W, Cun-Xin L, Tong X (2011). Molecular characterization and pathogenicity of swine influenza H9N2 subtype virus A/swine/HeBei/012/2008/(H9N2). Acta Virol, 55(3): 219–226

[49] Sandberg J K, Fast N M, Palacios E H, Fennelly G, Dobroszycki J, Palumbo P, Wiznia A, Grant R M, Bhardwaj N, Rosenberg M G, Nixon D F (2002). Selective loss of innate CD4(⁺) V alpha 24 natural killer T cells in human immunodeficiency virus infection. J Virol, 76(15): 7528–7534

[50] Schmieg J, Yang G, Franck R W, Tsuji M (2003). Superior protection against malaria and melanoma metastases by a C-glycoside analogue of the natural killer T cell ligand alpha-Galactosylceramide. J Exp Med, 198(11): 1631–1641

[51] Schmieg J, Yang G, Franck R W, Tsuji M (2010). A multifactorial mechanism in the superior antimalarial activity of alpha-C-GalCer. J Biomed Biotechnol, 2010: 283612

[52] Schofield L, Villaquiran J, Ferreira A, Schellekens H, Nussenzweig R, Nussenzweig V (1987). Gamma interferon, CD8⁺ T cells and antibodies required for immunity to malaria sporozoites. Nature, 330(6149): 664–666

[53] 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(2): 236–243

[54] Silk J D, Hermans I F, Gileadi U, Chong T W, Shepherd D, Salio M, Mathew B, Schmidt R R, Lunt S J, Williams K J, Stratford I J, Harris A L, Cerundolo V (2004). Utilizing the adjuvant properties of CD1d-dependent NK T cells in T cell-mediated immunotherapy. J Clin Invest, 114(12): 1800–1811

[55] Sriram V, Du W, Gervay-Hague J, Brutkiewicz R R (2005). Cell wall glycosphingolipids of Sphingomonas paucimobilis are CD1d-specific ligands for NKT cells. Eur J Immunol, 35(6): 1692–1701

[56] Sullivan B A, Kronenberg M (2005). Activation or anergy: NKT cells are stunned by alpha-galactosylceramide. J Clin Invest, 115(9): 2328–2329

[57] Teng M W, Westwood J A, Darcy P K, Sharkey J, Tsuji M, Franck R W, Porcelli S A, Besra G S, Takeda K, Yagita H, Kershaw M H, Smyth M J (2007). Combined natural killer T-cell based immunotherapy eradicates established tumors in mice. Cancer Res, 67(15): 7495–7504

[58] Thapa P, Zhang G, Xia C, Gelbard A, Overwijk W W, Liu C, Hwu P, Chang D Z, Courtney A, Sastry J K, Wang P G, Li C, Zhou D (2009). Nanoparticle formulated alpha-galactosylceramide activates NKT cells without inducing anergy. Vaccine, 27(25–26): 3484–3488

[59] Uldrich A P, Crowe N Y, Kyparissoudis K, Pellicci D G, Zhan Y, Lew A M, Bouillet P, Strasser A, Smyth M J, Godfrey D I (2005). NKT cell stimulation with glycolipid antigen in vivo: costimulation-dependent expansion, Bim-dependent contraction, and hyporesponsiveness to further antigenic challenge. J Immunol, 175(5): 3092–3101

[60] van der Vliet H J, von Blomberg B M, Hazenberg M D, Nishi N, Otto S A, van Benthem B H, Prins M, Claessen F A, van den Eertwegh A J, Giaccone G, Miedema F, Scheper R J, Pinedo H M (2002). Selective decrease in circulating V alpha 24⁺V beta 11⁺ NKT cells during HIV type 1 infection. J Immunol, 168(3): 1490–1495

[61] Vanderberg J P, Nussenzweig R S, Most H, Orton C G (1968). Protective immunity produced by the injection of x-irradiated sporozoites of Plasmodium berghei. II. Effects of radiation on sporozoites. J Parasitol, 54(6): 1175–1180

[62] Velmourougane G, Raju R, Bricard G, Im J S, Besra G S, Porcelli S A, Howell A R (2009). Synthesis and evaluation of an acyl-chain unsaturated analog of the Th2 biasing, immunostimulatory glycolipid, OCH. Bioorg Med Chem Lett, 19(13): 3386–3388

[63] Webster R G, Sharp G B, Claas E C (1995). Interspecies transmission of influenza viruses. Am J Respir Crit Care Med, 152(4 Pt 2): S25– S30

[64] Yamaguchi Y, Motoki K, Ueno H, Maeda K, Kobayashi E, Inoue H, Fukushima H, Koezuka Y (1996). Enhancing effects of (2S,3S,4R)-1-O-(alpha-D-galactopyranosyl)-2-(N-hexacosanoylamino) -1,3,4-octadecanetriol (KRN7000) on antigen-presenting function of antigen-presenting cells and antimetastatic activity of KRN7000-pretreated antigen-presenting cells. Oncol Res, 8(10–11): 399– 407

[65] Yang G, Schmieg J, Tsuji M, Franck R W (2004). The C-glycoside analogue of the immunostimulant alpha-galactosylceramide (KRN7000): synthesis and striking enhancement of activity. Angew Chem Int Ed Engl, 43(29): 3818–3822

[66] Yoshiga Y, Goto D, Segawa S, Ohnishi Y, Matsumoto I, Ito S, Tsutsumi A, Taniguchi M, Sumida T (2008). Invariant NKT cells produce IL-17 through IL-23-dependent and-independent pathways with potential modulation of Th17 response in collagen-induced arthritis. Int J Mol Med, 22(3): 369–374

[67] Yoshimoto T, Bendelac A, Watson C, Hu-Li J, Paul W E (1995). Role of NK1.1⁺ T cells in a TH2 response and in immunoglobulin E production. Science, 270(5243): 1845–1847

[68] Youn H J, Ko S Y, Lee K A, Ko H J, Lee Y S, Fujihashi K, Boyaka P N, Kim S H, Horimoto T, Kweon M N, Kang C Y (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(28): 5189–5198

[69] Yu E D, Girardi E, Wang J, Zajonc D M (2011). Cutting Edge: Structural basis for the recognition of β-linked glycolipid antigens by invariant NKT cells. J Immunol, 187(5): 2079–2083

[70] Zhou D, Mattner J, Cantu C 3rd, Schrantz N, Yin N, Gao Y, Sagiv Y, Hudspeth K, Wu Y P, Yamashita T, Teneberg S, Wang D, Proia R L, Levery S B, Savage P B, Teyton L, Bendelac A (2004). Lysosomal glycosphingolipid recognition by NKT cells. Science, 306(5702): 1786–1789

Acknowledgments

The authors have no competing financial interest. This work was supported by grants from the American Cancer Society, NIH/NCI K01 CA131487, R21 CA162273, R21 CA162277, and P30 Tumor Immunology and Immunotherapy Program to T J Webb. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute or the National Institutes of Health.

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