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The carboxypeptidase ACE shapes the MHC class I peptide repertoire

Nature Immunology volume 12, pages 1078–1085 (2011)Cite this article

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Abstract

The surface presentation of peptides by major histocompatibility complex (MHC) class I molecules is critical to CD8+ T cell–mediated adaptive immune responses. Aminopeptidases have been linked to the editing of peptides for MHC class I loading, but carboxy-terminal editing is thought to be due to proteasome cleavage. By analysis of wild-type mice and mice genetically deficient in or overexpressing the dipeptidase angiotensin-converting enzyme (ACE), we have now identified ACE as having a physiological role in the processing of peptides for MHC class I. ACE edited the carboxyl terminus of proteasome-produced MHC class I peptides. The lack of ACE exposed new antigens but also abrogated some self antigens. ACE had substantial effects on the surface expression of MHC class I in a haplotype-dependent manner. We propose a revised model of peptide processing for MHC class I by introducing carboxypeptidase activity into the process.

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Figure 1: ACE is upregulated during APC maturation.
Figure 2: The effect of ACE on surface expression of MHC class I.
Figure 3: ACE-deficient cells have normal MHC class I–peptide stability but more peptide supply.
Figure 4: The effect of ACE on the CD8+ T cell repertoire.
Figure 5: The effect of ACE in editing self antigens.
Figure 6: The effect of ACE on the presentation of viral antigens.
Figure 7: ACE works as a carboxyl dipeptidase on proteasome products.

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Acknowledgements

We thank S. Fuchs and E. Bernstein for vector construction; D. Roopenian and G. Christianson (Jackson Laboratories) for the minor histocompatibility CTL clones and assistance with cultures; G. Khitrov for assistance in liquid chromatography–mass spectrometry; G.E. Hammer for technical assistance with immunization; Q. Xu for assistance with RT-PCR; S. McLachlan (Cedars-Sinai Medical Center) for A20 cells; C. Ried (University of Munich) for Cd11c promoter DNA; R. Germain (US National Institutes of Health) for antibody 25D-1.16; R. Ahmed (Emory University) for L. monocytogenes strain EGD; and B. Taylor for administrative support. Supported by the US National Institutes of Health (R01 DK 039777 to K.E.B. and R01 CA 71971 to A.E.L.).

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Author notes

  1. Chentao Lin & Xu Chen

    Present address: Present address: Department of Immunology, Institute of Biotechnology, Fujian Academy of Agricultural Sciences, Fuzhou, Fujian, China.,

  2. Xiao Z Shen and Sandrine Billet: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California, USA

    Xiao Z Shen, Sandrine Billet, Chentao Lin, Derick Okwan-Duodu, Xu Chen & Kenneth E Bernstein

  2. Department of Pathology, Emory University School of Medicine, Atlanta, Georgia, USA

    Aron E Lukacher

  3. Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA

    Kenneth E Bernstein

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  1. Xiao Z Shen
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Contributions

X.Z.S., study conception and experimental design; X.Z.S. and S.B., experimental input, with assistance from C.L. (RT-PCR), D.O.-D. (L. monocytogenes infection) and X.C. (minigene construction); A.E.L., intellectual advice and reagents for polyomavirus experiments; K.E.B., intellectual advice and project coordination; X.Z.S. and K.E.B., manuscript authorship.

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Correspondence to Kenneth E Bernstein.

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Shen, X., Billet, S., Lin, C. et al. The carboxypeptidase ACE shapes the MHC class I peptide repertoire. Nat Immunol 12, 1078–1085 (2011). https://doi.org/10.1038/ni.2107

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