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Mechanism of CD1d-restricted natural killer T cell activation during microbial infection

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Abstract

CD1d-restricted natural killer T (NKT) cells are important for host defense against a variety of microbial pathogens. How and when these T cells become activated physiologically during infection remains unknown. Our data support a model in which NKT cells use a unique activation mechanism not requiring their recognition of microbial antigens. Instead, weak responses to CD1d-presented self antigens were amplified by interleukin 12 made by dendritic cells in response to microbial products, resulting in potent interferon-γ secretion. NKT cells were among the first lymphocytes to respond during Salmonella typhimurium infection, and their activation in vivo also depended on interleukin 12 and CD1d recognition. We propose this mechanism of activation as a major pathway responsible for the rapid activation of NKT cells in different microbial infections.

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Figure 1: Self-reactivity of CD1d-restricted T cell clones.
Figure 2: Activation of CD1d-restricted T cell clones by bacterial products.
Figure 3: Purified bacterial products activate CD1d-restricted T cell clones in the presence of DCs.
Figure 4: CD1d-restricted T cell activation by bacterial products is IL-12 dependent.
Figure 5: Self-reactivity of CD1d-restricted T cell clones is amplified by IL-12.
Figure 6: In vivo activation of CD1d-restricted T cells during S. typhimurium infection.
Figure 7: IFN-γ production by CD1d-restricted T cells during S. typhimurium infection is dependent on IL-12.

Change history

  • 02 November 2003

    appended supp info PDF with erratum PDF and placed footnote in SGML where references to Supplementary Table 3 occur

References

  1. Beckman, E.M. et al. Recognition of a lipid antigen by CD1-restricted αβ+ T cells. Nature 372, 691–694 (1994).

    Article  CAS  Google Scholar 

  2. Vincent, M.S., Gumperz, J.E. & Brenner, M.B. Understanding the function of CD1-restricted T cells. Nat. Immunol. 4, 517–523 (2003).

    Article  CAS  Google Scholar 

  3. Skold, M. & Behar, S.M. Role of CD1d-restricted NKT cells in microbial immunity. Infect. Immun. 71, 5447–5455 (2003).

    Article  Google Scholar 

  4. Nieuwenhuis, E.E. et al. CD1d-dependent macrophage-mediated clearance of Pseudomonas aeruginosa from lung. Nat. Med. 8, 588–593 (2002).

    Article  CAS  Google Scholar 

  5. Kawakami, K. et al. Activation of Vα14+ natural killer T cells by α-galactosylceramide results in development of Th1 response and local host resistance in mice infected with Cryptococcus neoformans. Infect. Immun. 69, 213–220 (2001).

    Article  CAS  Google Scholar 

  6. Duthie, M.S. et al. During Trypanosoma cruzi infection CD1d-restricted NK T cells limit parasitemia and augment the antibody response to a glycophosphoinositol-modified surface protein. Infect. Immun. 70, 36–48 (2002).

    Article  CAS  Google Scholar 

  7. Exley, M.A. et al. CD1d-reactive T-cell activation leads to amelioration of disease caused by diabetogenic encephalomyocarditis virus. J. Leukoc. Biol. 69, 713–718 (2001).

    CAS  PubMed  Google Scholar 

  8. Johnson, T.R., Hong, S., Van Kaer, L., Koezuka, Y. & Graham, B.S. NK T cells contribute to expansion of CD8+ T cells and amplification of antiviral immune responses to respiratory syncytial virus. J. Virol. 76, 4294–4303 (2002).

    Article  CAS  Google Scholar 

  9. Grubor-Bauk, B., Simmons, A., Mayrhofer, G. & Speck, P.G. Impaired clearance of herpes simplex virus type 1 from mice lacking CD1d or NKT cells expressing the semivariant Vα14-Jα281 TCR. J. Immunol. 170, 1430–1434 (2003).

    Article  CAS  Google Scholar 

  10. Ishigami, M. et al. The roles of intrahepatic Vα14+ NK1.1+ T cells for liver injury induced by Salmonella infection in mice. Hepatology 29, 1799–1808 (1999).

    Article  CAS  Google Scholar 

  11. 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).

    Article  CAS  Google Scholar 

  12. 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).

    Article  CAS  Google Scholar 

  13. Kawano, T. et al. CD1d-restricted and TCR-mediated activation of Vα14 NKT cells by glycosylceramides. Science 278, 1626–1629 (1997).

    Article  CAS  Google Scholar 

  14. Bendelac, A., Rivera, M.N., Park, S.H. & Roark, J.H. Mouse CD1-specific NK1 T cells: development, specificity, and function. Annu. Rev. Immunol. 15, 535–562 (1997).

    Article  CAS  Google Scholar 

  15. Davodeau, F. et al. Close phenotypic and functional similarities between human and murine αβ T cells expressing invariant TCR α-chains. J. Immunol. 158, 5603–5611 (1997).

    CAS  PubMed  Google Scholar 

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

    Article  CAS  Google Scholar 

  17. Exley, M., Garcia, J., Balk, S.P. & Porcelli, S. Requirements for CD1d recognition by human invariant Vα24+ CD4CD8 T cells. J. Exp. Med. 186, 109–120 (1997).

    Article  CAS  Google Scholar 

  18. van Der Vliet, H.J. et al. Human natural killer T cells acquire a memory-activated phenotype before birth. Blood 95, 2440–2442 (2000).

    CAS  PubMed  Google Scholar 

  19. Park, S.H., Benlagha, K., Lee, D., Balish, E. & Bendelac, A. Unaltered phenotype, tissue distribution and function of Vα14+ NKT cells in germ-free mice. Eur. J. Immunol. 30, 620–625 (2000).

    Article  CAS  Google Scholar 

  20. Gumperz, J.E. et al. Murine CD1d-restricted T cell recognition of cellular lipids. Immunity 12, 211–221 (2000).

    Article  CAS  Google Scholar 

  21. Moody, D.B. et al. Structural requirements for glycolipid antigen recognition by CD1b-restricted T cells. Science 278, 283–286 (1997).

    Article  CAS  Google Scholar 

  22. Moody, D.B. et al. CD1c-mediated T-cell recognition of isoprenoid glycolipids in Mycobacterium tuberculosis infection. Nature 404, 884–888 (2000).

    Article  CAS  Google Scholar 

  23. Folch, J., Lees, M. & Sloane-Staneley, G.H. A simple method for the isolation and purification of total lipides from animal tissues. J. Biol. Chem. 226, 497–509 (1957).

    CAS  PubMed  Google Scholar 

  24. Hamilton, S., Hamilton, R.J. & Sewell, P.A. Extraction of lipids and derivative formation. in Lipid Analysis: a Practical Approach (eds. Hamilton, R.J. and Hamilton, S.) 13–63 (IRL Press at Oxford University, Oxford, 1992).

    Google Scholar 

  25. Medzhitov, R. & Janeway, C. Jr. The Toll receptor family and microbial recognition. Trends. Microbiol. 8, 452–456 (2000).

    Article  CAS  Google Scholar 

  26. Okamura, H. et al. Cloning of a new cytokine that induces IFN-γ production by T cells. Nature 378, 88–91 (1995).

    Article  CAS  Google Scholar 

  27. Gracie, J.A., Robertson, S.E. & McInnes, I.B. Interleukin-18. J. Leukoc. Biol. 73, 213–224 (2003).

    Article  CAS  Google Scholar 

  28. McSorley, S.J., Cookson, B.T. & Jenkins, M.K. Characterization of CD4+ T cell responses during natural infection with Salmonella typhimurium. J. Immunol. 164, 986–993 (2000).

    Article  CAS  Google Scholar 

  29. Mittrucker, H.W. & Kaufmann, S.H. Immune response to infection with Salmonella typhimurium in mice. J. Leukoc. Biol. 67, 457–463 (2000).

    Article  CAS  Google Scholar 

  30. McSorley, S.J., Asch, S., Costalonga, M., Reinhardt, R.L. & Jenkins, M.K. Tracking salmonella-specific CD4 T cells in vivo reveals a local mucosal response to a disseminated infection. Immunity 16, 365–377 (2002).

    Article  CAS  Google Scholar 

  31. 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).

    Article  CAS  Google Scholar 

  32. Eberl, G. & MacDonald, H.R. Rapid death and regeneration of NKT cells in anti-CD3ε- or IL-12-treated mice: a major role for bone marrow in NKT cell homeostasis. Immunity 9, 345–353 (1998).

    Article  CAS  Google Scholar 

  33. Osman, Y. et al. Activation of hepatic NKT cells and subsequent liver injury following administration of α-galactosylceramide. Eur. J. Immunol. 30, 1919–1928 (2000).

    Article  CAS  Google Scholar 

  34. 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).

    CAS  PubMed  Google Scholar 

  35. DeFranco, A.L. B-lymphocyte activation. in Fundamental Immunology (ed. Paul, W.E.) 225–261 (Lippincott-Raven Publishers, Philadelphia, 1999).

    Google Scholar 

  36. 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).

    Article  CAS  Google Scholar 

  37. Balk, S.P., Bleicher, P.A. & Terhorst, C. Isolation and characterization of a cDNA and gene coding for a fourth CD1 molecule. Proc. Natl. Acad. Sci. USA 86, 252–256 (1989).

    Article  CAS  Google Scholar 

  38. Takebe, Y. et al. SR α promoter: an efficient and versatile mammalian cDNA expression system composed of the simian virus 40 early promoter and the R-U5 segment of human T-cell leukemia virus type 1 long terminal repeat. Mol. Cell. Biol. 8, 466–472 (1988).

    Article  CAS  Google Scholar 

  39. Shimizu, Y. & DeMars, R. Production of human cells expressing individual transferred HLA-A,-B,-C genes using an HLA-A,-B,-C null human cell line. J. Immunol. 142, 3320–3328 (1989).

    CAS  PubMed  Google Scholar 

  40. Lozzio, B.B. & Lozzio, C.B. Properties and usefulness of the original K-562 human myelogenous leukemia cell line. Leuk. Res. 3, 363–370 (1979).

    Article  CAS  Google Scholar 

  41. Michetti, P., Mahan, M.J., Slauch, J.M., Mekalanos, J.J. & Neutra, M.R. Monoclonal secretory immunoglobulin A protects mice against oral challenge with the invasive pathogen Salmonella typhimurium. Infect. Immun. 60, 1786–1792 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank M.S. Vincent for reading the manuscript. Supported by the Charles A. King Trust of the Medical Foundation (J.E.G.), Howard Hughes Medical Institute (L.B.), the Juvenile Diabetes Research Foundation Islet Transplantation Center at Harvard Medical School (S.C.K.) and the National Institutes of Health (R37AI29873 and RO1AI48932 to M.B.B.).

*Note: In the version of Supplementary Table 3 originally published online to accompany this article, an incorrect standard deviation value was given. The bottom row should read "14 (6.3)" in the column for liver, day 2. This error has been corrected for the HTML version of this article online. The correction has been appended to the PDF version online.

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Correspondence to Michael B Brenner.

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Supplementary information

Supplementary Table 1 (PDF 67 kb)

Supplementary Table 2 (PDF 75 kb)

Supplementary Table 3

*Note: In the version of Supplementary Table 3 originally published online to accompany this article, an incorrect standard deviation value was given. The bottom row should read "14 (6.3)" in the column for liver, day 2. This error has been corrected for the HTML version of this article online. The correction has been appended to the PDF version online. (PDF 113 kb)

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Brigl, M., Bry, L., Kent, S. et al. Mechanism of CD1d-restricted natural killer T cell activation during microbial infection. Nat Immunol 4, 1230–1237 (2003). https://doi.org/10.1038/ni1002

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