A Multifactorial Mechanism in the Superior Antimalarial Activity of Alpha-C-GalCer

Overview

Journal J Biomed Biotechnol

Specialty Biology

Date 2010 Jan 14

PMID 20069056

Citations 6

Authors

John Schmieg

Guangli Yang

Richard W Franck

Moriya Tsuji

Affiliations

Soon will be listed here.

Abstract

We have previously shown that the C-glycoside analog of alpha-galactosylceramide (alpha-GalCer), alpha-C-GalCer, displays a superior inhibitory activity against the liver stages of the rodent malaria parasite Plasmodium yoelii than its parental glycolipid, alpha-GalCer. In this study, we demonstrate that NK cells, as well as IL-12, are a key contributor for the superior activity displayed by alpha-C-GalCer. Surprisingly, the diminished production of Th2 cytokines, including IL-4, by alpha-C-GalCer has no affect on its superior therapeutic activity relative to alpha-GalCer. Finally, we show that the in vivo administration of alpha-C-GalCer induces prolonged maturation of dendritic cells (DCs), as well as an enhanced proliferative response of mouse invariant Valpha14 (Valpha14i) NKT cells, both of which may also contribute to some degree to the superior activity of alpha-C-GalCer in vivo.

Citing Articles

Can invariant Natural Killer T cells drive B cell fate? a look at the humoral response.

Palacios P, Santibanez A, Aguirre-Munoz F, Gutierrez-Vera C, Nino de Zepeda-Carrizo V, Gongora-Pimentel M Front Immunol. 2025; 16:1505883.

PMID: 40040714 PMC: 11876049. DOI: 10.3389/fimmu.2025.1505883.

Effects of Invariant NKT Cells on Parasite Infections and Hygiene Hypothesis.

Yang J, Zhou Y, Singh R J Immunol Res. 2016; 2016:2395645.

PMID: 27563682 PMC: 4987483. DOI: 10.1155/2016/2395645.

Adjuvants in the Driver's Seat: How Magnitude, Type, Fine Specificity and Longevity of Immune Responses Are Driven by Distinct Classes of Immune Potentiators.

Bergmann-Leitner E, Leitner W Vaccines (Basel). 2015; 2(2):252-96.

PMID: 26344620 PMC: 4494256. DOI: 10.3390/vaccines2020252.

Synthesis of C-5″ and C-6″-modified α-GalCer analogues as iNKT-cell agonists.

Guillaume J, Pauwels N, Aspeslagh S, Zajonc D, Elewaut D, Van Calenbergh S Bioorg Med Chem. 2015; 23(13):3175-82.

PMID: 26003341 PMC: 4461518. DOI: 10.1016/j.bmc.2015.04.068.

Boosting the Immune Response: The Use of iNKT cell ligands as vaccine adjuvants.

Subrahmanyam P, Webb T Front Biol (Beijing). 2012; 7(5):436-444.

PMID: 23264781 PMC: 3524977. DOI: 10.1007/s11515-012-1194-2.

References

Yang G, Schmieg J, Tsuji M, Franck R . The C-glycoside analogue of the immunostimulant alpha-galactosylceramide (KRN7000): synthesis and striking enhancement of activity. Angew Chem Int Ed Engl. 2004; 43(29):3818-22. DOI: 10.1002/anie.200454215. View

Schumann J, Voyle R, Wei B, MacDonald H . Cutting edge: influence of the TCR V beta domain on the avidity of CD1d:alpha-galactosylceramide binding by invariant V alpha 14 NKT cells. J Immunol. 2003; 170(12):5815-9. DOI: 10.4049/jimmunol.170.12.5815. View

Schmieg J, Gonzalez-Aseguinolaza G, Tsuji M . The role of natural killer T cells and other T cell subsets against infection by the pre-erythrocytic stages of malaria parasites. Microbes Infect. 2003; 5(6):499-506. DOI: 10.1016/s1286-4579(03)00072-8. View

Singh A, Wilson M, Hong S, Olivares-Villagomez D, Du C, Stanic A . Natural killer T cell activation protects mice against experimental autoimmune encephalomyelitis. J Exp Med. 2001; 194(12):1801-11. PMC: 2193577. DOI: 10.1084/jem.194.12.1801. View

Gonzalez-Aseguinolaza G, de Oliveira C, Tomaska M, Hong S, Bruna-Romero O, Nakayama T . alpha -galactosylceramide-activated Valpha 14 natural killer T cells mediate protection against murine malaria. Proc Natl Acad Sci U S A. 2000; 97(15):8461-6. PMC: 26970. DOI: 10.1073/pnas.97.15.8461. View

Rachmilewitz J, Lanzavecchia A . A temporal and spatial summation model for T-cell activation: signal integration and antigen decoding. Trends Immunol. 2002; 23(12):592-5. DOI: 10.1016/s1471-4906(02)02342-6. View

Cai Z, Kishimoto H, Brunmark A, Jackson M, Peterson P, Sprent J . Requirements for peptide-induced T cell receptor downregulation on naive CD8+ T cells. J Exp Med. 1997; 185(4):641-51. PMC: 2196147. DOI: 10.1084/jem.185.4.641. View

Rosette C, Werlen G, Daniels M, Holman P, Alam S, Travers P . The impact of duration versus extent of TCR occupancy on T cell activation: a revision of the kinetic proofreading model. Immunity. 2001; 15(1):59-70. DOI: 10.1016/s1074-7613(01)00173-x. View

Bruna-Romero O, Hafalla J, Gonzalez-Aseguinolaza G, Sano G, Tsuji M, Zavala F . Detection of malaria liver-stages in mice infected through the bite of a single Anopheles mosquito using a highly sensitive real-time PCR. Int J Parasitol. 2001; 31(13):1499-502. DOI: 10.1016/s0020-7519(01)00265-x. View

10.

OGarra A, Arai N . The molecular basis of T helper 1 and T helper 2 cell differentiation. Trends Cell Biol. 2000; 10(12):542-50. DOI: 10.1016/s0962-8924(00)01856-0. View

11.

Wilson M, Johansson C, Olivares-Villagomez D, Singh A, Stanic A, Wang C . The response of natural killer T cells to glycolipid antigens is characterized by surface receptor down-modulation and expansion. Proc Natl Acad Sci U S A. 2003; 100(19):10913-8. PMC: 196902. DOI: 10.1073/pnas.1833166100. View

12.

Kitamura H, Iwakabe K, Yahata T, Nishimura S, Ohta A, Ohmi Y . The natural killer T (NKT) cell ligand alpha-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. 1999; 189(7):1121-8. PMC: 2193012. DOI: 10.1084/jem.189.7.1121. View

13.

Fujii S, Shimizu K, Hemmi H, Fukui M, Bonito A, Chen G . 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. 2006; 103(30):11252-7. PMC: 1544074. DOI: 10.1073/pnas.0604812103. View

14.

Stanic A, Shashidharamurthy R, Bezbradica J, Matsuki N, Yoshimura Y, Miyake S . Another view of T cell antigen recognition: cooperative engagement of glycolipid antigens by Va14Ja18 natural T(iNKT) cell receptor [corrected]. J Immunol. 2003; 171(9):4539-51. DOI: 10.4049/jimmunol.171.9.4539. View

15.

Fujii S, Shimizu K, Smith C, Bonifaz L, Steinman R . Activation of natural killer T cells by alpha-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. 2003; 198(2):267-79. PMC: 2194082. DOI: 10.1084/jem.20030324. View

16.

Ma X, Sartori A, Trinchieri G . Molecular mechanisms of the induction of IL-12 and its inhibition by IL-10. J Immunol. 1998; 160(12):5936-44. View

17.

Smyth M, Crowe N, Godfrey D . NK cells and NKT cells collaborate in host protection from methylcholanthrene-induced fibrosarcoma. Int Immunol. 2001; 13(4):459-63. DOI: 10.1093/intimm/13.4.459. View

18.

Tomura M, Yu W, Ahn H, Yamashita M, Yang Y, Ono S . A novel function of Valpha14+CD4+NKT cells: stimulation of IL-12 production by antigen-presenting cells in the innate immune system. J Immunol. 1999; 163(1):93-101. View

19.

Kronenberg M . Toward an understanding of NKT cell biology: progress and paradoxes. Annu Rev Immunol. 2005; 23:877-900. DOI: 10.1146/annurev.immunol.23.021704.115742. View

20.

Valitutti S, Lanzavecchia A . Serial triggering of TCRs: a basis for the sensitivity and specificity of antigen recognition. Immunol Today. 1997; 18(6):299-304. View