Cryptic MHC-E epitope from influenza elicits a potent cytolytic T cell response

doi:10.1038/s41590-023-01644-5

. 2023 Nov;24(11):1933-1946.

doi: 10.1038/s41590-023-01644-5. Epub 2023 Oct 12.

Cryptic MHC-E epitope from influenza elicits a potent cytolytic T cell response

Michael J Hogan¹, Nikita Maheshwari^{2

3

4}, Bridget E Begg⁵, Annalisa Nicastri⁶, Emma J Hedgepeth², Hiromi Muramatsu⁷, Norbert Pardi⁷, Michael A Miller^{8

9}, Shanelle P Reilly¹⁰, Laurent Brossay¹⁰, Kristen W Lynch⁵, Nicola Ternette⁶, Laurence C Eisenlohr^{11

12}

Affiliations

¹ Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, PA, USA. mihogan@upenn.edu.
² Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
³ School of Arts and Sciences, University of Pennsylvania, Philadelphia, PA, USA.
⁴ Department of Pathology, University of Chicago, Chicago, IL, USA.
⁵ Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
⁶ The Jenner Institute, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
⁷ Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
⁸ Department of Microbiology and Immunology, Thomas Jefferson University, Philadelphia, PA, USA.
⁹ Century Therapeutics, Philadelphia, PA, USA.
¹⁰ Department of Molecular Microbiology and Immunology, Brown University, Providence, RI, USA.
¹¹ Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, PA, USA. eisenlc@pennmedicine.upenn.edu.
¹² Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. eisenlc@pennmedicine.upenn.edu.

PMID: 37828378
DOI: 10.1038/s41590-023-01644-5

Cryptic MHC-E epitope from influenza elicits a potent cytolytic T cell response

Michael J Hogan et al. Nat Immunol. 2023 Nov.

. 2023 Nov;24(11):1933-1946.

doi: 10.1038/s41590-023-01644-5. Epub 2023 Oct 12.

Authors

Affiliations

¹ Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, PA, USA. mihogan@upenn.edu.
² Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
³ School of Arts and Sciences, University of Pennsylvania, Philadelphia, PA, USA.
⁴ Department of Pathology, University of Chicago, Chicago, IL, USA.
⁵ Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
⁶ The Jenner Institute, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
⁷ Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
⁸ Department of Microbiology and Immunology, Thomas Jefferson University, Philadelphia, PA, USA.
⁹ Century Therapeutics, Philadelphia, PA, USA.
¹⁰ Department of Molecular Microbiology and Immunology, Brown University, Providence, RI, USA.
¹¹ Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, PA, USA. eisenlc@pennmedicine.upenn.edu.
¹² Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. eisenlc@pennmedicine.upenn.edu.

PMID: 37828378
DOI: 10.1038/s41590-023-01644-5

Abstract

The extent to which unconventional forms of antigen presentation drive T cell immunity is unknown. By convention, CD8 T cells recognize viral peptides, or epitopes, in association with classical major histocompatibility complex (MHC) class I, or MHC-Ia, but immune surveillance can, in some cases, be directed against peptides presented by nonclassical MHC-Ib, in particular the MHC-E proteins (Qa-1 in mice and HLA-E in humans); however, the overall importance of nonclassical responses in antiviral immunity remains unclear. Similarly uncertain is the importance of 'cryptic' viral epitopes, defined as those undetectable by conventional mapping techniques. Here we used an immunopeptidomic approach to search for unconventional epitopes that drive T cell responses in mice infected with influenza virus A/Puerto Rico/8/1934. We identified a nine amino acid epitope, termed M-SL9, that drives a co-immunodominant, cytolytic CD8 T cell response that is unconventional in two major ways: first, it is presented by Qa-1, and second, it has a cryptic origin, mapping to an unannotated alternative reading frame product of the influenza matrix gene segment. Presentation and immunogenicity of M-SL9 are dependent on the second AUG codon of the positive sense matrix RNA segment, suggesting translation initiation by leaky ribosomal scanning. During influenza virus A/Puerto Rico/8/1934 infection, M-SL9-specific T cells exhibit a low level of egress from the lungs and strong differentiation into tissue-resident memory cells. Importantly, we show that M-SL9/Qa-1-specific T cells can be strongly induced by messenger RNA vaccination and that they can mediate antigen-specific cytolysis in vivo. Our results demonstrate that noncanonical translation products can account for an important fraction of the T cell repertoire and add to a growing body of evidence that MHC-E-restricted T cells could have substantial therapeutic value.

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References

1. Hansen, S. G. et al. Immune clearance of highly pathogenic SIV infection. Nature 502, 100–104 (2013). - PubMed - PMC - DOI
1. Hansen, S. G. et al. A live-attenuated RhCMV/SIV vaccine shows long-term efficacy against heterologous SIV challenge. Sci. Transl. Med. 11, eaaw2607 (2019). - PubMed - PMC - DOI
1. Malouli, D. et al. Cytomegaloviral determinants of CD8⁺ T cell programming and RhCMV/SIV vaccine efficacy. Sci. Immunol. 6, eabg5413 (2021). - PubMed - PMC - DOI
1. Hansen, S. G. et al. Myeloid cell tropism enables MHC-E–restricted CD8⁺ T cell priming and vaccine efficacy by the RhCMV/SIV vaccine. Sci. Immunol. 7, eabn9301 (2022). - PubMed - PMC - DOI
1. Anderson, C. K., Reilly, E. C., Lee, A. Y. & Brossay, L. Qa-1-restricted CD8⁺ T cells can compensate for the absence of conventional T cells during viral infection. Cell Rep. 27, 537–548 (2019). - PubMed - PMC - DOI

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[1] Hansen, S. G. et al. Immune clearance of highly pathogenic SIV infection. Nature 502, 100–104 (2013). - PubMed - PMC - DOI

[2] Hansen, S. G. et al. Immune clearance of highly pathogenic SIV infection. Nature 502, 100–104 (2013). - PubMed - PMC - DOI

[3] Hansen, S. G. et al. A live-attenuated RhCMV/SIV vaccine shows long-term efficacy against heterologous SIV challenge. Sci. Transl. Med. 11, eaaw2607 (2019). - PubMed - PMC - DOI

[4] Hansen, S. G. et al. A live-attenuated RhCMV/SIV vaccine shows long-term efficacy against heterologous SIV challenge. Sci. Transl. Med. 11, eaaw2607 (2019). - PubMed - PMC - DOI

[5] Malouli, D. et al. Cytomegaloviral determinants of CD8⁺ T cell programming and RhCMV/SIV vaccine efficacy. Sci. Immunol. 6, eabg5413 (2021). - PubMed - PMC - DOI

[6] Malouli, D. et al. Cytomegaloviral determinants of CD8⁺ T cell programming and RhCMV/SIV vaccine efficacy. Sci. Immunol. 6, eabg5413 (2021). - PubMed - PMC - DOI

[7] Hansen, S. G. et al. Myeloid cell tropism enables MHC-E–restricted CD8⁺ T cell priming and vaccine efficacy by the RhCMV/SIV vaccine. Sci. Immunol. 7, eabn9301 (2022). - PubMed - PMC - DOI

[8] Hansen, S. G. et al. Myeloid cell tropism enables MHC-E–restricted CD8⁺ T cell priming and vaccine efficacy by the RhCMV/SIV vaccine. Sci. Immunol. 7, eabn9301 (2022). - PubMed - PMC - DOI

[9] Anderson, C. K., Reilly, E. C., Lee, A. Y. & Brossay, L. Qa-1-restricted CD8⁺ T cells can compensate for the absence of conventional T cells during viral infection. Cell Rep. 27, 537–548 (2019). - PubMed - PMC - DOI

[10] Anderson, C. K., Reilly, E. C., Lee, A. Y. & Brossay, L. Qa-1-restricted CD8⁺ T cells can compensate for the absence of conventional T cells during viral infection. Cell Rep. 27, 537–548 (2019). - PubMed - PMC - DOI

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Cryptic MHC-E epitope from influenza elicits a potent cytolytic T cell response

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Cryptic MHC-E epitope from influenza elicits a potent cytolytic T cell response

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