Abstract
Immunosurveillance by cytotoxic T cells requires that cells generate a diverse spectrum of peptides for presentation by major histocompatibility complex (MHC) class I molecules. Those peptides are generated by proteolysis, which begins in the cytoplasm and continues in the endoplasmic reticulum by the unique aminopeptidase ERAAP. The overall extent to which trimming by ERAAP modifies the peptide pool and the immunological consequences of ERAAP deficiency are unknown. Here we show that the peptide-MHC repertoire of ERAAP-deficient mice was missing many peptides. Furthermore, ERAAP-deficient cells presented many unstable and structurally unique peptide-MHC complexes, which elicited potent CD8+ T cell and B cell responses. Thus, ERAAP is a 'quintessential editor' of the peptide-MHC repertoire and, paradoxically, its absence enhances immunogenicity.
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Acknowledgements
Supported by the US National Institutes of Health (N.S.).
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G.E.H. contributed to the experimental design, immunized mice, did experiments, screened hybridomas, analyzed data and cowrote the manuscript; F.G. generated and backcrossed ERAAP-deficient mice and generated the WEko hybridomas and the biotinylated derivative of WEko.70; E.J. contributed to the experimental design and did skin grafts; H.N. sorted cells; and N.S. established the initial scientific questions, provided guidance and cowrote the manuscript.
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Supplementary information
Supplementary Fig. 1
Model to explain the origin and immunogenicity of unedited, novel pMHC I expressed by ERAAP-deficient cells. (PDF 402 kb)
Supplementary Fig. 2
The CD8+ T cell alloresponse to Kbm-1 MHC class I expressing cells is comparable to BEko T and ERAAP-deficient anti-WT CD8+ T cell responses. (PDF 824 kb)
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Hammer, G., Gonzalez, F., James, E. et al. In the absence of aminopeptidase ERAAP, MHC class I molecules present many unstable and highly immunogenic peptides. Nat Immunol 8, 101–108 (2007). https://doi.org/10.1038/ni1409
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DOI: https://doi.org/10.1038/ni1409
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