Abstract

Natural killer T cells (NKT cells) recognize glycolipid antigens presented by CD1d. These cells express an evolutionarily conserved, invariant T cell antigen receptor (TCR), but the forces that drive TCR conservation have remained uncertain. Here we show that NKT cells recognized diacylglycerol-containing glycolipids from Streptococcus pneumoniae, the leading cause of community-acquired pneumonia, and group B Streptococcus, which causes neonatal sepsis and meningitis. Furthermore, CD1d-dependent responses by NKT cells were required for activation and host protection. The glycolipid response was dependent on vaccenic acid, which is present in low concentrations in mammalian cells. Our results show how microbial lipids position the sugar for recognition by the invariant TCR and, most notably, extend the range of microbes recognized by this conserved TCR to several clinically important bacteria.

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Acknowledgements

We thank S. Akira (Osaka University) for Myd88−/− mice; B. Beutler (Scripps Research Institute) for Myd88−/−TrifLps2/Lps2 mice; M. Antony (University of Birmingham) for group B Streptococcus A909; N. Yamamoto, T. Kinjo, G.D. Ainge, D. Gibson and G. Painter for suggestions; N. Sato for help with glycolipid analysis; and C. Lena for technical assistance. Supported by the US National Institutes of Health (AI45053 and AI71922 to M.K., AI074952 to D.M.Z.; AI070258 to M.T.; and F32AI083029 to J.L.V.), the Japan Society for the Promotion of Science and Ministry of Education, Culture, Sports, Science and Technology (22689031), the Ministry of Health, Labor and Welfare of Japan (H22seisakusouyakuippan012), the Uehara Memorial Foundation (Y.Ki.), the Wellcome Trust, the Royal Society, J. Bardrick (G.S.B.) and the Cancer Research Institute (D.M.Z.).

Author information

Author notes

    • Yuki Kinjo
    • , Petr Illarionov
    •  & José Luis Vela

    These authors contributed equally to this work.

Affiliations

  1. Division of Developmental Immunology, La Jolla Institute for Allergy & Immunology, La Jolla, California, USA.

    • Yuki Kinjo
    • , José Luis Vela
    • , Bo Pei
    • , Archana Khurana
    •  & Mitchell Kronenberg
  2. Department of Chemotherapy and Mycoses, National Institute of Infectious Diseases, Tokyo, Japan.

    • Yuki Kinjo
    • , Yukihiro Kaneko
    • , Akiko Okawara
    •  & Yoshitsugu Miyazaki
  3. School of Biosciences, University of Birmingham, Edgbaston, Birmingham, UK.

    • Petr Illarionov
    •  & Gurdyal S Besra
  4. Division of Cell Biology, La Jolla Institute for Allergy & Immunology, La Jolla, California, USA.

    • Enrico Girardi
    • , Yali Li
    •  & Dirk M Zajonc
  5. HIV and Malaria Vaccine Program, Aaron Diamond AIDS Research Center, Affiliate of the Rockefeller University, New York, New York, USA.

    • Xiangming Li
    •  & Moriya Tsuji
  6. Department of Chemistry and Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, California, USA.

    • Masakazu Imamura
    •  & Chi-Huey Wong
  7. Division of Infectious Diseases, Department of Medicine, University of British Columbia, Vancouver, Canada.

    • Anaximandro Gómez-Velasco
  8. Kyowa Hakko Kirin California Inc, La Jolla, California, USA.

    • Paul Rogers
  9. Department of Pediatrics and Skaggs School of Pharmacy & Pharmaceutical Sciences, University of California, San Diego, La Jolla, California, USA.

    • Samira Dahesh
    • , Satoshi Uchiyama
    •  & Victor Nizet
  10. Department of Applied Material and Life Science, College of Engineering, Kanto Gakuin University, Yokohama, Japan.

    • Kazuyoshi Kawahara
  11. Department of Infection, Immunity and Inflammation, University of Leicester, Leicester, UK.

    • Hasan Yesilkaya
    •  & Peter W Andrew
  12. Department of Medical Microbiology, Mycology and Immunology, Tohoku University Graduate School of Medicine, Sendai, Japan.

    • Kazuyoshi Kawakami

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Contributions

Y. Kinjo and M.K. designed most the study, except D.M.Z. designed the crystal structure study and the Biacore assay; Y. Kinjo, P.I., J.L.V., E.G., V.N., D.M.Z. and M.K. prepared the manuscript; Y. Kinjo, J.L.V. and B.P. did most of the immunology experiments; P.I., K. Kawahara and A.G.-V. analyzed bacterial glycolipids; P.I., M.I. and C.-H.W. synthesized glycolipids; G.S.B. provided informational support; E.G., Y.L. and D.M.Z. determined the crystal structure of the CD1d-Glc-DAG-s2 complex and did the Biacore assay; X.L., P.R. and M.T. did the human NKT cell experiments; Y. Kinjo, J.L.V., Y. Kaneko, A.O., Y.M. and K. Kawakami did S. pneumoniae infection experiments; S.D., S.U. and V.N. prepared bacterial sonicates and provided advice on bacterial culture and infection; A.K. made the mouse CD1d protein; H.Y. and P.W.A. prepared bacteria for glycolipid analysis; and M.K. provided overall supervision.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Mitchell Kronenberg.

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DOI

https://doi.org/10.1038/ni.2096

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