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Invariant natural killer T cells recognize glycolipids from pathogenic Gram-positive bacteria

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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Figure 1: CD1d-dependent cytokine production by Vα14i NKT cells.
Figure 2: Structure of S. pneumoniae glycolipids.
Figure 3: Microbial glycolipids stimulate Vα14i NKT cells in vitro.
Figure 4: In vivo stimulation of Vα14i NKT cells by purified glycolipids.
Figure 5: Stringent requirement for vaccenic acid in the stimulation of iNKT cells.
Figure 6: Crystal structure of the mouse CD1d–Glc-DAG-s2 complex.

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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.).

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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.

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Correspondence to Mitchell Kronenberg.

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Kinjo, Y., Illarionov, P., Vela, J. et al. Invariant natural killer T cells recognize glycolipids from pathogenic Gram-positive bacteria. Nat Immunol 12, 966–974 (2011). https://doi.org/10.1038/ni.2096

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