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Lipid length controls antigen entry into endosomal and nonendosomal pathways for CD1b presentation

Nature Immunology volume 3, pages 435–442 (2002)Cite this article

Abstract

CD1 proteins present various glycolipid antigens to T cells, but the cellular mechanisms that control which particular glycolipids generate T cell responses are not understood. We show here that T cell recognition of glucose monomycolate antigens with long (C80) alkyl chains involves the delivery of CD1b proteins and antigens to late endosomes in a process that takes several hours. In contrast, analogs of the same antigen with shorter (C32) alkyl chains are rapidly, but inefficiently, presented by cell surface CD1b proteins. Dendritic cells (DCs) preferentially present long-chain glycolipids, which results, in part, from their rapid internalization and selective delivery of antigens to endosomal compartments. Nonprofessional antigen-presenting cells, however, preferentially present short-chain glycolipids because of their lack of prominent endosomal presentation pathways. Because long alkyl chain length distinguishes certain microbial glycolipids from common mammalian glycolipids, these findings suggest that DCs use a specialized endosomal-loading pathway to promote preferential recognition of glycolipids with a more intrinsically foreign structure.

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Figure 1: CD1b-mediated T cell activation by GMM antigens of varying alkyl chain length.
Figure 2: DCs internalized GMM antigens and selectively delivered C80 GMM to late endosomal and lysosomal compartments.
Figure 3: B lymphoblastoid cells and DCs differed in the efficiency of uptake and presentation of GMM alkyl chain length analogs.
Figure 4: Presentation of GMMs with short alkyl chains was more rapid, but less stable, than presentation of GMMs with longer alkyl chains.
Figure 5: Presentation of GMM chain length analogs by cells expressing CD1b proteins that lack endosomal targeting sequences.
Figure 6: Transformed thymocytes more efficiently presented C32 GMM.

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Acknowledgements

We thank J. Gumperz, J. Hartt, M. Brenner and M. Sugita for advice and reagents; D. Olive for the 4A7 hybridoma cell line; P. Chavrier for the Rab5 antiserum; and I. Wilson and B. Segelke for molecular modeling studies of CD1 proteins. Supported by grants from the American College of Rheumatology Research and Education Foundation, the Human Frontiers Science Program, the Irene Diamond Foundation, NIAMS (ARO1988 to D. B. M.), the NIAID (AI49313, AI45889, AI48933, AI 31044 and AI 38960 to D. B. M., S. A. P. and M. L. T.), the NCI (CA74958 to M. L. T) and the Medical Research Council (49343 and G0000895 to G. S. B.).

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Authors and Affiliations

  1. Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital and Harvard Medical School, Smith Building Room 514, 1 Jimmy Fund Way, Boston, 02115, MA, USA

    D. Branch Moody, Tan-Yun Cheng & Carme Roura-Mir

  2. Department of Microbiology and Immunology, Albert Einstein College of Medicine, Room 416 Forchheimer Building, 1300 Morris Park Avenue, Bronx, 10461, NY, USA

    Volker Briken & Steven A. Porcelli

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

    Mark R. Guy & Gurdyal S. Besra

  4. Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, 20892, MD, USA

    David H. Geho

  5. Department of Pathology, University of Pennsylvania, 6 Gates Pavillion, 3400 Spruce Street, Philadelphia, 19104, PA, USA

    Mark L. Tykocinski

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Correspondence to D. Branch Moody.

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S. Porcelli is a paid consultant of Antigenics, a publicly held biotechnology company that also supports research in his laboratory. Antigenics is a licensee of several patents related to the application of antigen presentation by CD1 and has a commercial interest in further scientific development in this area.

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Moody, D., Briken, V., Cheng, TY. et al. Lipid length controls antigen entry into endosomal and nonendosomal pathways for CD1b presentation. Nat Immunol 3, 435–442 (2002). https://doi.org/10.1038/ni780

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