Exogenous and endogenous glycolipid antigens activate NKT cells during microbial infections (original) (raw)

Nature volume 434, pages 525–529 (2005)Cite this article

A Corrigendum to this article was published on 26 January 2006

Abstract

CD1d-restricted natural killer T (NKT) cells are innate-like lymphocytes that express a conserved T-cell receptor and contribute to host defence against various microbial pathogens1,2. However, their target lipid antigens have remained elusive. Here we report evidence for microbial, antigen-specific activation of NKT cells against Gram-negative, lipopolysaccharide (LPS)-negative alpha-Proteobacteria such as Ehrlichia muris and Sphingomonas capsulata. We have identified glycosylceramides from the cell wall of Sphingomonas that serve as direct targets for mouse and human NKT cells, controlling both septic shock reaction and bacterial clearance in infected mice. In contrast, Gram-negative, LPS-positive Salmonella typhimurium activates NKT cells through the recognition of an endogenous lysosomal glycosphingolipid, iGb3, presented by LPS-activated dendritic cells. These findings identify two novel antigenic targets of NKT cells in antimicrobial defence, and show that glycosylceramides are an alternative to LPS for innate recognition of the Gram-negative, LPS-negative bacterial cell wall.

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References

  1. Park, S. H. & Bendelac, A. CD1-restricted T-cell responses and microbial infection. Nature 406, 788–792 (2000)
    Article CAS Google Scholar
  2. Brigl, M. & Brenner, M. B. CD1: antigen presentation and T cell function. Annu. Rev. Immunol. 22, 817–890 (2004)
    Article CAS Google Scholar
  3. 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)
    Article CAS Google Scholar
  4. Nieuwenhuis, E. E. et al. CD1d-dependent macrophage-mediated clearance of Pseudomonas aeruginosa from lung. Nature Med. 8, 588–593 (2002)
    Article CAS Google Scholar
  5. 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)
    Article CAS Google Scholar
  6. 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)
    Article CAS Google Scholar
  7. 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)
    Article ADS CAS Google Scholar
  8. Lin, M. & Rikihisa, Y. Ehrlichia chaffeensis and Anaplasma phagocytophilum lack genes for lipid A biosynthesis and incorporate cholesterol for their survival. Infect. Immun. 71, 5324–5331 (2003)
    Article CAS Google Scholar
  9. Kawahara, K., Moll, H., Knirel, Y. A., Seydel, U. & Zahringer, U. Structural analysis of two glycosphingolipids from the lipopolysaccharide-lacking bacterium Sphingomonas capsulata. Eur. J. Biochem. 267, 1837–1846 (2000)
    Article CAS Google Scholar
  10. Hoebe, K. et al. Identification of Lps2 as a key transducer of MyD88-independent TIR signalling. Nature 424, 743–748 (2003)
    Article ADS CAS Google Scholar
  11. Zhou, D. et al. Lysosomal glycosphingolipid recognition by NKT cells. Science 306, 1786–1789 (2004)
    Article ADS CAS Google Scholar
  12. Proia, R. L. Glycosphingolipid functions: insights from engineered mouse models. Phil. Trans. R. Soc. Lond. B 358, 879–883 (2003)
    Article CAS Google Scholar
  13. Keusch, J. J., Manzella, S. M., Nyame, K. A., Cummings, R. D. & Baenziger, J. U. Expression cloning of a new member of the ABO blood group glycosyltransferases, iGb3 synthase, that directs the synthesis of isoglobo-glycosphingolipids. J. Biol. Chem. 275, 25308–25314 (2000)
    Article CAS Google Scholar
  14. Amano, K. et al. Deficiency of peptidoglycan and lipopolysaccharide components in Rickettsia tsutsugamushi. Infect. Immun. 55, 2290–2292 (1987)
    CAS PubMed PubMed Central Google Scholar
  15. 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)
    Article CAS Google Scholar
  16. Hsueh, P. R. et al. Nosocomial infections caused by Sphingomonas paucimobilis: clinical features and microbiological characteristics. Clin. Infect. Dis. 26, 676–681 (1998)
    Article CAS Google Scholar
  17. 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)
    Article CAS Google Scholar
  18. Selmi, C. et al. Patients with primary biliary cirrhosis react against a ubiquitous xenobiotic-metabolizing bacterium. Hepatology 38, 1250–1257 (2003)
    Article CAS Google Scholar
  19. Olano, J. P. & Walker, D. H. Human ehrlichioses. Med. Clin. North Am. 86, 375–392 (2002)
    Article Google Scholar
  20. von Loewenich, F. D., Scorpio, D. G., Reischl, U., Dumler, J. S. & Bogdan, C. Frontline: control of Anaplasma phagocytophilum, an obligate intracellular pathogen, in the absence of inducible nitric oxide synthase, phagocyte NADPH oxidase, tumor necrosis factor, Toll-like receptor (TLR)2 and TLR4, or the TLR adaptor molecule MyD88. Eur. J. Immunol. 34, 1789–1797 (2004)
    Article CAS Google Scholar
  21. 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)
    Article CAS Google Scholar
  22. 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)
    Article CAS Google Scholar
  23. Ismail, N. et al. Overproduction of TNF-α by CD8+ type 1 cells and down-regulation of IFN-γ production by CD4+ Th1 cells contribute to toxic shock-like syndrome in an animal model of fatal monocytotropic ehrlichiosis. J. Immunol. 172, 1786–1800 (2004)
    Article CAS Google Scholar
  24. Bendelac, A., Hunziker, R. D. & Lantz, O. Increased interleukin 4 and immunoglobulin E production in transgenic mice overexpressing NK1 T cells. J. Exp. Med. 184, 1285–1293 (1996)
    Article CAS Google Scholar

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Acknowledgements

We thank D. Wei for reading the manuscript, K. Thompson for help with biochemical characterization of Sphingomonas and growth of bacteria, S. Porcelli for the gift of anti-human CD1d, R. Duggan, J. Marvin and B. Eisfelder for cell sorting, L. Taylor for managing the mouse colonies, and the University of Chicago Digestive Disease Research center for equipment. Supported by NIH grants to A.B., P.S.B. and L.T., an NIH award to K.L.D. and O.S., an NIH grant to B.B., a Cancer Research Institute fellowship to J.M. and D.Z., and a fellowship from the Fondation pour la Recherche Medicale to P.S.-M.Authors' contributions P.B.S. and A.B. are co-senior authors.

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Author notes

  1. Paul B. Savage and Albert Bendelac: These authors contributed equally to this work

Authors and Affiliations

  1. Committee on Immunology, University of Chicago, Chicago, Illinois, 60637, USA
    Jochen Mattner, Dapeng Zhou, Pierre Saint-Mezard, Vivien Wang & Albert Bendelac
  2. Committee on Microbiology, University of Chicago, Chicago, Illinois, 60637, USA
    Kristin L. DeBord & Olaf Schneewind
  3. Department of Pathology, University of Texas Medical Branch, Galveston, Texas, 77555, USA
    Nahed Ismail & David Walker
  4. Department of Chemistry and Biochemistry, Brigham Young University, Provo, Utah, 84602-5700, USA
    Randal D. Goff, Ying Gao, Ning Yin & Paul B. Savage
  5. Department of Immunology, The Scripps Research Institute, La Jolla, California, 92037, USA
    Carlos Cantu III, Kasper Hoebe, Bruce Beutler & Luc Teyton

Authors

  1. Jochen Mattner
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  2. Kristin L. DeBord
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  3. Nahed Ismail
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  4. Randal D. Goff
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  5. Carlos Cantu III
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  6. Dapeng Zhou
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  7. Pierre Saint-Mezard
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  8. Vivien Wang
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  9. Ying Gao
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  10. Ning Yin
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  11. Kasper Hoebe
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  12. Olaf Schneewind
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  13. David Walker
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  14. Bruce Beutler
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  15. Luc Teyton
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  16. Paul B. Savage
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  17. Albert Bendelac
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Corresponding authors

Correspondence toPaul B. Savage or Albert Bendelac.

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Supplementary information

Supplementary Figure S1

Cell divisions of NKT cells in response to bacterial stimuli or 100ng/ml αGalCer, as indicated, six days after stimulation (NS, no stimulus). Upper row, CD1d- αGalCer/B220 staining of spleen cells with NKT cell gate and percentage as indicated; lower row, CFSE dilution profile of 5 × 103 gated NKT cells. (PDF 283 kb)

Supplementary Figure S2

IFN-γ released by whole spleen cells of indicated genotypes cultured with heat killed Salmonella typhimurium, Sphingomonas capsulata and Ehrlichia muris for 48 hours. Data shown as percentage of control wild type. Mean and SD of two to three separate experiments. (PDF 78 kb)

Supplementary Figure S3

Bacterial burden in the lungs of CD1d+/- and _CD1d_-/- mice at different days after infection with 1 × 106 CFU of Sphingomonas (each bar represents mean and SD of four to five mice). Fold increase and p values are indicated. (PDF 124 kb)

Supplementary Figure S4

Acute lethality after inoculation of 5 × 108 Sphingomonas capsulata to Jα18+/- and _Jα18_-/- mice (_n_=12 each, _p_= 0.034). (PDF 54 kb)

Supplementary Figure S5

Acute serum release of p40 after infection with 1 × 107 Sphingomonas capsulata in heterozygous and homozygous Jα18 mutant mice. Similar results were obtained in two independent experiments. (PDF 75 kb)

Supplementary Figure S6

Ehrlichia PCR counts in lungs and livers of CD1+/- and _CD1_-/- mice recovered at day 2 and day 7 post-infection (each bar shows mean and SD of three mice). Fold increase and p values are indicated. One experiment representative of two is shown. (PDF 203 kb)

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Mattner, J., DeBord, K., Ismail, N. et al. Exogenous and endogenous glycolipid antigens activate NKT cells during microbial infections.Nature 434, 525–529 (2005). https://doi.org/10.1038/nature03408

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