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In the absence of aminopeptidase ERAAP, MHC class I molecules present many unstable and highly immunogenic peptides

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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Figure 1: ERAAP-deficient mice elicit a CD8+ T cell response to autosomal antigens expressed on wild-type cells.
Figure 2: ERAAP-deficient mice lack peptides normally expressed in the pMHC I repertoire of wild-type cells.
Figure 3: C57BL/6J wild-type mice elicit a robust CD8+ T cell response to ERAAP-deficient cells.
Figure 4: Wild-type CD8+ T cells responding to ERAAP-deficient cells (BEko T cells) are specific for ligands expressed on ERAAP-deficient cells in a TAP- and H-2b-dependent way.
Figure 5: Ligands for BEko T cells but not those for wild-type-specific ERAAP-deficient CD8+ T cells are unstable.
Figure 6: BEko T cells are specific for precursors of self peptides that are N-terminally extended and presented by H-2Kb or H-2Db MHC class I molecules.
Figure 7: ERAAP-deficient cells express a large volume of structurally unique pMHC I complexes.

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Acknowledgements

Supported by the US National Institutes of Health (N.S.).

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Authors and Affiliations

Authors

Contributions

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.

Corresponding author

Correspondence to Nilabh Shastri.

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The authors declare no competing financial interests.

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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