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Thymocyte expression of cathepsin L is essential for NKT cell development

Nature Immunology volume 3, pages 1069–1074 (2002)Cite this article

Abstract

CD1d antigen presentation to natural killer T (NKT) cells expressing the semi-invariant T cell receptor Vα14Jα18 requires CD1d trafficking through endosomal compartments; however, the endosomal events remain undefined. We show that mice lacking the endosomal protease cathepsin L (catL) have greatly reduced numbers of Vα14+NK1.1+ T cells. In addition, catL expression in thymocytes is critical not only for selection of these cells in vivo but also for stimulation of Vα14+NK1.1+ T cells in vitro. CD1d cell-surface expression and intracellular localization appear normal in catL-deficient thymocytes, as does the lysosomal morphology; this implies a specific role for catL in regulating presentation of natural CD1d ligands mediating Vα14+NK1.1+ T cell selection. These data implicate lysosomal proteases as key regulators of not only classical major histocompatibility complex class II antigen presentation but also nonclassical CD1d presentation.

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Figure 1: Impaired selection of Vα14+ NKT cells in catL-deficient mice.
Figure 2: Impaired stimulation of a Vα14+ NKT cell hybridoma by catL-deficient thymocytes.
Figure 3: CatL-deficient thymocytes exhibit normal cellular distribution and endosomal morphology.
Figure 4: Analysis of Vα14+ NKT cell selection in bone marrow–chimeric mice.
Figure 5: CatL-deficient thymocytes gain functional catL in vivo in the presence of catL-sufficient thymic stroma.

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Acknowledgements

Supported by the Howard Hughes Medical Institute (K. H. and A. R.) and the National Institute of Health (A. R. and A. B.), American Cancer Society (A. B.), NOW (M. J. K. grant 805-48-014) and the Leukemia and Lymphoma Society of America (K. B.). We thank G. Gillard, J. Griffith, C. Hsieh and P. Gough for excellent technical assistance, helpful discussions and critical review of the manuscript. R. Scriwanek and M. van Peski helped with the photography.

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Author notes

  1. Karen Honey and Kamel Benlagha: These authors contributed equally to this work.

Authors and Affiliations

  1. Howard Hughes Medical Institute and Department of Immunology, University of Washington School of Medicine, Seattle, 98195, WA, USA

    Karen Honey, Courtney Beers, Katherine Forbush & Alexander Y. Rudensky

  2. Department of Molecular Biology, Princeton University, Princeton, 08544, NJ, USA

    Kamel Benlagha & Albert Bendelac

  3. Department of Immunology, Scripps Research Institute, La Jolla, 92037, CA, USA

    Luc Teyton

  4. Department of Cell Biology, UMC Utrecht, Heidelberglaan 100, 3584 CX, Utrecht, The Netherlands

    Monique J. Kleijmeer

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Correspondence to Alexander Y. Rudensky.

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Honey, K., Benlagha, K., Beers, C. et al. Thymocyte expression of cathepsin L is essential for NKT cell development. Nat Immunol 3, 1069–1074 (2002). https://doi.org/10.1038/ni844

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