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HLA polymorphisms

Oyez, Oyez, Oyez!

Nature Immunology volume 24, pages 1052–1053 (2023)Cite this article

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Presentation of signal peptides by HLA-E to natural killer cells prevents cell lysis via interactions with the inhibitory CD94–NKG2A receptor. A study now reveals an unexpected level of sophistication and heterogeneity in this receptor–ligand interaction.

If the immune system had town criers reporting on the status of their streets, they would be the human leukocyte antigen class I (HLA-I) molecules. Among these, the non-classical HLA-E molecule presents peptides derived from the signal sequences of other HLA-I molecules. Recognition of HLA-E–signal peptide complexes by the inhibitory receptor CD94–NKG2A prevents natural killer (NK) cell lysis of target cells, whereas disruption of HLA processing and HLA-E expression removes this brake to allow NK cell activation. In this issue of Nature Immunology, Lin et al.1 explore the effects of signal peptide variation to show that not all are created equal, with signal peptides most able to stabilize HLA-E expression not necessarily facilitating the strongest CD94–NKG2A interactions1. This satiating ‘soup to nuts’ study provides insights into how genetic variation across individuals regulates HLA-E recognition, which in itself is increasingly being recognized as an important regulator of outcomes in viral infection and cancer.

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Fig. 1: Recognition of HLA-E–signal peptide complexes by CD94–NKG2A.

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Acknowledgements

During the drafting of the article, Brinley John, the father of Jamie Rossjohn, passed away.

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Authors and Affiliations

  1. Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, Victoria, Australia

    Philippa M. Saunders & Andrew G. Brooks

  2. Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Melbourne, Australia

    Jamie Rossjohn

  3. Institute of Infection and Immunity, Cardiff University, School of Medicine, Cardiff, UK

    Jamie Rossjohn

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  1. Philippa M. Saunders
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  2. Andrew G. Brooks
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  3. Jamie Rossjohn
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Correspondence to Jamie Rossjohn.

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Saunders, P.M., Brooks, A.G. & Rossjohn, J. Oyez, Oyez, Oyez!. Nat Immunol 24, 1052–1053 (2023). https://doi.org/10.1038/s41590-023-01541-x

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