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A CD74-dependent MHC class I endolysosomal cross-presentation pathway

Nature Immunology volume 13, pages 237245 (2012) | Download Citation

Abstract

Immune responses are initiated and primed by dendritic cells (DCs) that cross-present exogenous antigen. The chaperone CD74 (invariant chain) is thought to promote DC priming exclusively in the context of major histocompatibility complex (MHC) class II. However, we demonstrate here a CD74-dependent MHC class I cross-presentation pathway in DCs that had a major role in the generation of MHC class I–restricted, cytolytic T lymphocyte (CTL) responses to viral protein– and cell-associated antigens. CD74 associated with MHC class I in the endoplasmic reticulum of DCs and mediated the trafficking of MHC class I to endolysosomal compartments for loading with exogenous peptides. We conclude that CD74 has a previously undiscovered physiological function in endolysosomal DC cross-presentation for priming MHC class I–mediated CTL responses.

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Acknowledgements

We thank D. Mathis (Institut de Génétique et de Biologie Moléculaire et Cellulaire and The Harvard Stem Cell Institute) for Cd74−/− (H-2Kb) mice; N. Shastri (University of California, Berkeley) for the B3Z T cell hybridoma; J. Yewdell (US National Institutes of Health) for antibody 25.D1.16; I. Shachar (Weizmann Institute of Sciences) for the CD74 constructs; and B. Barber and D. Williams (University of Toronto) for antiserum directed toward the region of H-2Kb encoded by exon 8. Supported by the Canadian Institutes of Health Research (K.O.; and MOP-77631 and MOP-86739 to W.A.J.).

Author information

Author notes

    • Genc Basha
    •  & Anna T Reinicke

    Present addresses: Nanomedicine Research Unit, Department of Biochemistry and Molecular Biology, Life Sciences Institute, University of British Columbia, British Columbia, Vancouver, Canada (G.B.), and Institute for Systemic Inflammation Research, University of Lübeck, Lübeck, Germany (A.T.R.).

    • Genc Basha
    •  & Kyla Omilusik

    These authors contributed equally to this work.

Affiliations

  1. The Biomedical Research Centre, The Michael Smith Laboratories, The Centre for Blood Research, The Brain Research Centre, Department of Microbiology and Immunology, Department of Medical Genetics and Department of Zoology, University of British Columbia, Vancouver, Canada.

    • Genc Basha
    • , Kyla Omilusik
    • , Ana Chavez-Steenbock
    • , Anna T Reinicke
    • , Nathan Lack
    • , Kyung Bok Choi
    •  & Wilfred A Jefferies

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Contributions

G.B. and K.O. designed, did and analyzed experiments; A.C.S. did DC-transfection experiments; A.T.R. did experiments and provided intellectual input; N.L. provided intellectual input and bioinformatics; K.B.C. did experiments; W.A.J. conceived of the research project, designed experiments, supervised the research and analyzed the data; and G.B., K.O. and W.A.J. wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Wilfred A Jefferies.

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DOI

https://doi.org/10.1038/ni.2225

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