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Targeting MHC-E as a new strategy for vaccines and immunotherapeutics

Nature Reviews Immunology (2025)Cite this article

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Abstract

MHC-E is a highly conserved, non-polymorphic MHC protein that engages inhibitory and activating receptors on natural killer (NK) cells and T cells and can also present antigens to T cell receptors. NK cell responses driven by activating receptor interactions with MHC-E are implicated in controlling chronic viral infections and cancer. Immunotherapeutic targeting of interactions between MHC-E and inhibitory receptors to increase the activation of NK cells and T cells shows promise in improving antitumour immune responses. Furthermore, MHC-E-restricted CD8+ T cells elicited by cytomegalovirus-based vaccines might, for certain infections and cancers, be more effective than CD8+ T cells restricted by classical MHC class I or class II molecules. The ability of MHC-E to regulate or mediate both innate and adaptive immune responses independently of the MHC haplotype of an individual raises the possibility of new, universally effective vaccines and immunotherapies for infectious disease and cancer. Although the therapeutic exploitation of MHC-E is still in its infancy, recent advances in the understanding of MHC-E biology show enormous potential, as described in this Review.

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Fig. 1: Innate and adaptive receptors for HLA-E.
Fig. 2: Targeting HLA-E-expressing tumour cells or infected cells.
Fig. 3: Loading of HLA-E with non-VL9 peptides.

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Acknowledgements

The authors thank A. Townsend for the help with figures and graphics. The authors acknowledge funding by the National Institutes of Health: R01 AI175459 to K.F., P.B., G.M.G., A.J.M. and L.J.P.; P01AI174856 to K.F. and L.J.P.; P51 OD011092 to K.F. and L.J.P.; UM1 AI164567 to P.B., G.M.G. and A.J.M.; and UM1 AI144371 to P.B. and A.J.M.; by the National Institute for Health and Care Research: NIHR 203339 to P.B.; by the Wellcome Trust: 227388/Z/23/Z to G.M.G. and A.J.M.; and by the Gates Foundation: INV-055780 to G.M.G. and A.J.M.

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Authors and Affiliations

  1. Vaccine & Gene Therapy Institute, Oregon Health & Science University, Beaverton, OR, USA

    Klaus Früh & Louis J. Picker

  2. Centre for Immuno-Oncology, Nuffield Department of Medicine, University of Oxford, Oxford, UK

    Persephone Borrow, Geraldine M. Gillespie & Andrew J. McMichael

Authors
  1. Klaus Früh
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  2. Persephone Borrow
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  3. Geraldine M. Gillespie
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The authors contributed equally to all aspects of the article.

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Correspondence to Klaus Früh or Louis J. Picker.

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Competing interests

Oregon Health & Science University (OHSU), L.J.P. and K.F. have a substantial financial interest in Vir Biotechnology, Inc., a company that may have a commercial interest in the results of this research and technology. L.J.P. and K.F. are inventors of technology licensed to Vir Biotechnology. These potential individual and institutional conflicts of interest have been reviewed and managed by OHSU. A.J.M. and G.M.G. are inventors on HLA-E-related patents owned by Oxford University Innovation. A.J.M. and G.M.G. are cofounders of E-Biotherapy Ltd, a dormant company with a potential commercial interest in this research and technology.

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Nature Reviews Immunology thanks Michael Hogan, Amir Horowitz and Thorbald Van Hall for their contribution to the peer review of this work.

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Früh, K., Borrow, P., Gillespie, G.M. et al. Targeting MHC-E as a new strategy for vaccines and immunotherapeutics. Nat Rev Immunol (2025). https://doi.org/10.1038/s41577-025-01218-6

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