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Cytomegalovirus US2 destroys two components of the MHC class II pathway, preventing recognition by CD4+ T cells

Nature Medicine volume 5, pages 1039–1043 (1999)Cite this article

Abstract

Human cytomegalovirus (HCMV) is a ubiquitous herpesvirus that causes life-threatening disease in patients who are immunosuppressed for bone marrow or tissue transplantation or who have AIDS (ref. 1). HCMV establishes lifelong latent infections and, after periodic reactivation from latency, uses a panel of immune evasion proteins to survive and replicate in the face of robust, fully primed host immunity2,3. Monocyte/macrophages are important host cells for HCMV, serving as a latent reservoir and as a means of dissemination throughout the body4. Macrophages and other HCMV-permissive cells, such as endothelial and glial cells, can express MHC class II proteins and present antigens to CD4+ T lymphocytes. Here, we show that the HCMV protein US2 causes degradation of two essential proteins in the MHC class II antigen presentation pathway: HLA-DR-α and DM-α. This was unexpected, as US2 has been shown to cause degradation of MHC class I (refs. 5,6), which has only limited homology with class II proteins. Expression of US2 in cells reduced or abolished their ability to present antigen to CD4+ T lymphocytes. Thus, US2 may allow HCMV-infected macrophages to remain relatively 'invisible' to CD4+ T cells, a property that would be important after virus reactivation.

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Figure 1: MHC class II expression is reduced in HCMV-infected cells.
Figure 2: US2 induces degradation of class II-α chains by proteasomes without a cytoplasmic intermediate and binds to class II proteins.
Figure 3: US2 induces degradation of HLA-DM.
Figure 4: US2 inhibits presentation of exogenous antigen to CD4+ T cells.

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Acknowledgements

We thank B. Walters, J. DeKoning, K. Fish and C. Soderberg-Naucler for supplying preliminary data and advice in the early stages of this work and M. Bogyo, D. Kavanagh and J. Trowsdale for reagents and antibodies. The work was supported by NIH grants EY11245 to D.C.J., AI24178 to J.A.N. and AI41754 to S.R.R. and AI01644 to D.M.L.

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Author notes

  1. Jessica Boname

    Present address: Department of Pathology, Cambridge University, Cambridge, UK

Authors and Affiliations

  1. Department of Molecular Microbiology & Immunology, Oregon Health Sciences University, Portland, 97201, Oregon, USA

    Roman Tomazin, Jessica Boname, Nagendra R. Hegde, Jay A. Nelson & David C. Johnson

  2. Division of Pulmonary and Critical Care Medicine, Portland VA Medical Center, Portland, 97207, Oregon, USA

    David M. Lewinsohn

  3. Department of Anatomy, University of California, San Francisco, 94143, California, USA

    Yoram Altschuler

  4. Department of Molecular Biology, Wyeth-Ayerst Research, Pearl River, 10965, New York, USA

    Thomas R. Jones

  5. Section of Immunobiology, Howard Hughes Medical Institute, Yale University, New Haven, 06510, Connecticut, USA

    Peter Cresswell

  6. Fred Hutchinson Cancer Research Center, Seattle, 98104, Washington, USA

    Stanley R. Riddell

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Tomazin, R., Boname, J., Hegde, N. et al. Cytomegalovirus US2 destroys two components of the MHC class II pathway, preventing recognition by CD4+ T cells. Nat Med 5, 1039–1043 (1999). https://doi.org/10.1038/12478

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