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CD1c-mediated T-cell recognition of isoprenoid glycolipids in Mycobacterium tuberculosis infection

Nature volume 404, pages 884–888 (2000)Cite this article

Abstract

The discovery of the CD1 antigen presentation pathway has expanded the spectrum of T-cell antigens to include lipids1,2,3,4, but the range of natural lipid antigens and functions of CD1-restricted T cells in vivo remain poorly understood. Here we show that the T-cell antigen receptor and the CD1c protein mediate recognition of an evolutionarily conserved family of isoprenoid glycolipids whose members include essential components of protein glycosylation and cell-wall synthesis pathways. A CD1c-restricted, mycobacteria-specific T-cell line recognized two previously unknown mycobacterial hexosyl-1-phosphoisoprenoids and structurally related mannosyl-β1-phosphodolichols. Responses to mannosyl-β1-phosphodolichols were common among CD1c-restricted T-cell lines and peripheral blood T lymphocytes of human subjects recently infected with M. tuberculosis, but were not seen in naive control subjects. These results define a new class of broadly distributed lipid antigens presented by the CD1 system during infection in vivo and suggest an immune mechanism for recognition of senescent or transformed cells that are known to have altered dolichol lipids.

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Figure 1: Molecular requirements for T-cell recognition of a hexosyl phospholipid (HPL) antigen.
Figure 2: Structures of natural CD1c-presented mycobacterial isoprenoid glycolipids.
Figure 3: Fine specificity of human CD1c-restricted T-cell lines for mannosyl phosphodolichol.
Figure 4: CD1c-restricted MPD-specific immune responses occur in humans with M. tuberculosis infection.

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Acknowledgements

The authors thank P. Brennan, B. Wolucka, D. Crick, J. Rush, C. Waechter, D. Olive and S. Krag for advice, support and the provision of reagents. A. Kusai provided high-energy mass spectra and high-resolution ESI–MS measurements. D. E. Frederique, S.-Y. Chan and T. Y. Cheng provided technical support. This work is supported by grants from the NIH (NIAMS, NIAID, NCRR), the Lister Institute of Preventive Medicine, the Mizutani Foundation for Glycoscience, the Deutsche Forschungsgemeinschaft and the American College of Rheumatology Research and Education Foundation.

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Author notes

  1. Timo Ulrichs

    Present address: Department of Microbiology and Immunology The Medical School, University of Newcastle Upon Tyne, Framlington Place, Newcastle upon Tyne, NE2 4HH, UK

  2. Sudagar S. Gurcha

    Present address: Department of Microbiology and Immunology, Albert Einstein College of Medicine, Room 416 Forchheimer Building, 1300 Morris Park Avenue, Bronx, New York, 10461, USA

Authors and Affiliations

  1. Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital and Harvard Medical School, Boston, 02115, Massachusetts, USA

    D. Branch Moody, Timo Ulrichs, Ethan Grant, Jean-Pierre Rosat, Michael B. Brenner & Steven A. Porcelli

  2. Mass Spectrometry Resource, Boston University School of Medicine, Boston, 02118, Massachusetts , USA

    Walter Mühlecker, David C. Young & Catherine E. Costello

  3. Department of Microbiology and Immunology The Medical School, University of Newcastle Upon Tyne, Framlington Place, Newcastle upon Tyne, NE2 4HH, UK

    Gurdyal S. Besra & Steven A. Porcelli

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Correspondence to D. Branch Moody.

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Moody, D., Ulrichs, T., Mühlecker, W. et al. CD1c-mediated T-cell recognition of isoprenoid glycolipids in Mycobacterium tuberculosis infection. Nature 404, 884–888 (2000). https://doi.org/10.1038/35009119

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