The human cytomegalovirus-encoded pUS28 antagonizes CD4+ T cell recognition by targeting CIITA
Human cytomegalovirus (HCMV) is a relevant pathogen, especially for individuals with impaired immunity. Harnessing potent immune antagonists, HCMV circumvents sterile immunity. Given that HCMV prevents the upregulation of human leukocyte antigen (HLA)-DP and HLA-DR, we screened a library of HCMV gen...
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eLife Sciences Publications Ltd
2025-07-01
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| Online Access: | https://elifesciences.org/articles/96414 |
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| author | Fabienne Maassen Vu Thuy Khanh Le-Trilling Luisa Betke Thilo Bracht Corinna Siegmund Malte Bayer Benjamin Katschinski Antonia Belter Tanja Becker Denise Mennerich Sebastian Voigt Lori Frappier Barbara Sitek Katharina Fleischhauer Mirko Trilling |
| author_facet | Fabienne Maassen Vu Thuy Khanh Le-Trilling Luisa Betke Thilo Bracht Corinna Siegmund Malte Bayer Benjamin Katschinski Antonia Belter Tanja Becker Denise Mennerich Sebastian Voigt Lori Frappier Barbara Sitek Katharina Fleischhauer Mirko Trilling |
| author_sort | Fabienne Maassen |
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| description | Human cytomegalovirus (HCMV) is a relevant pathogen, especially for individuals with impaired immunity. Harnessing potent immune antagonists, HCMV circumvents sterile immunity. Given that HCMV prevents the upregulation of human leukocyte antigen (HLA)-DP and HLA-DR, we screened a library of HCMV genes by co-expression with the HLA class II (HLA-II)-inducing transcription coordinator class II transactivator (CIITA). We identified the latency regulator pUS28 as an interaction factor and potent viral antagonist of CIITA-driven expression of CD74, HLA-DR, HLA-DM, HLA-DQ, and HLA-DP. Both wt-pUS28 and a mutant incapable of inducing G protein-coupled signaling (R129A), but not a mutant lacking the C-terminus, drastically reduced the CIITA protein abundance post-transcriptionally. While control CD4 + T cells from HCMV-seropositive individuals vigorously responded to CIITA-expressing cells decorated with HCMV antigens, pUS28 expression was sufficient to inhibit HLA-II induction and immune recognition by HCMV-specific CD4 + T cells. Our data uncover pUS28 to be employed by HCMV to evade HLA-II-mediated recognition by CD4 + T cells. |
| format | Article |
| id | doaj-art-7d13baad636e4cb4ac2c27cba3bb1f95 |
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| language | English |
| publishDate | 2025-07-01 |
| publisher | eLife Sciences Publications Ltd |
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| spelling | doaj-art-7d13baad636e4cb4ac2c27cba3bb1f952025-07-03T15:01:46ZengeLife Sciences Publications LtdeLife2050-084X2025-07-011410.7554/eLife.96414The human cytomegalovirus-encoded pUS28 antagonizes CD4+ T cell recognition by targeting CIITAFabienne Maassen0https://orcid.org/0009-0004-3535-3727Vu Thuy Khanh Le-Trilling1https://orcid.org/0000-0002-2733-3732Luisa Betke2https://orcid.org/0009-0008-6767-6239Thilo Bracht3Corinna Siegmund4https://orcid.org/0000-0002-1371-0779Malte Bayer5https://orcid.org/0000-0003-1060-8856Benjamin Katschinski6https://orcid.org/0000-0002-1314-2820Antonia Belter7https://orcid.org/0009-0005-4409-1447Tanja Becker8Denise Mennerich9Sebastian Voigt10Lori Frappier11Barbara Sitek12Katharina Fleischhauer13Mirko Trilling14https://orcid.org/0000-0003-3659-3541Institute for Virology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany; Institute for Experimental Cellular Therapy, University Hospital Essen, University of Duisburg-Essen, Essen, GermanyInstitute for Virology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany; Institute for the Research on HIV and AIDS‐associated Diseases, University Hospital Essen, University of Duisburg-Essen, Essen, GermanyInstitute for Experimental Cellular Therapy, University Hospital Essen, University of Duisburg-Essen, Essen, GermanyMedizinisches Proteom Center, Ruhr University Bochum, Bochum, Germany; Department of Anesthesia, Intensive Care Medicine and Pain Therapy, University Hospital Knappschaftskrankenhaus Bochum, Bochum, GermanyInstitute for Virology, University Hospital Essen, University of Duisburg-Essen, Essen, GermanyMedizinisches Proteom Center, Ruhr University Bochum, Bochum, Germany; Department of Anesthesia, Intensive Care Medicine and Pain Therapy, University Hospital Knappschaftskrankenhaus Bochum, Bochum, GermanyInstitute for Virology, University Hospital Essen, University of Duisburg-Essen, Essen, GermanyInstitute for Virology, University Hospital Essen, University of Duisburg-Essen, Essen, GermanyInstitute for Virology, University Hospital Essen, University of Duisburg-Essen, Essen, GermanyInstitute for Virology, University Hospital Essen, University of Duisburg-Essen, Essen, GermanyInstitute for Virology, University Hospital Essen, University of Duisburg-Essen, Essen, GermanyDepartment of Molecular Genetics, University of Toronto, Toronto, CanadaMedizinisches Proteom Center, Ruhr University Bochum, Bochum, Germany; Department of Anesthesia, Intensive Care Medicine and Pain Therapy, University Hospital Knappschaftskrankenhaus Bochum, Bochum, GermanyInstitute for Experimental Cellular Therapy, University Hospital Essen, University of Duisburg-Essen, Essen, Germany; German Cancer Consortium (DKTK), partner site Essen/Düsseldorf, Heidelberg, GermanyInstitute for Virology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany; Institute for the Research on HIV and AIDS‐associated Diseases, University Hospital Essen, University of Duisburg-Essen, Essen, GermanyHuman cytomegalovirus (HCMV) is a relevant pathogen, especially for individuals with impaired immunity. Harnessing potent immune antagonists, HCMV circumvents sterile immunity. Given that HCMV prevents the upregulation of human leukocyte antigen (HLA)-DP and HLA-DR, we screened a library of HCMV genes by co-expression with the HLA class II (HLA-II)-inducing transcription coordinator class II transactivator (CIITA). We identified the latency regulator pUS28 as an interaction factor and potent viral antagonist of CIITA-driven expression of CD74, HLA-DR, HLA-DM, HLA-DQ, and HLA-DP. Both wt-pUS28 and a mutant incapable of inducing G protein-coupled signaling (R129A), but not a mutant lacking the C-terminus, drastically reduced the CIITA protein abundance post-transcriptionally. While control CD4 + T cells from HCMV-seropositive individuals vigorously responded to CIITA-expressing cells decorated with HCMV antigens, pUS28 expression was sufficient to inhibit HLA-II induction and immune recognition by HCMV-specific CD4 + T cells. Our data uncover pUS28 to be employed by HCMV to evade HLA-II-mediated recognition by CD4 + T cells.https://elifesciences.org/articles/96414Human cytomegalovirusHCMVhuman herpesvirus 5HHV-5US28HLA class II |
| spellingShingle | Fabienne Maassen Vu Thuy Khanh Le-Trilling Luisa Betke Thilo Bracht Corinna Siegmund Malte Bayer Benjamin Katschinski Antonia Belter Tanja Becker Denise Mennerich Sebastian Voigt Lori Frappier Barbara Sitek Katharina Fleischhauer Mirko Trilling The human cytomegalovirus-encoded pUS28 antagonizes CD4+ T cell recognition by targeting CIITA eLife Human cytomegalovirus HCMV human herpesvirus 5 HHV-5 US28 HLA class II |
| title | The human cytomegalovirus-encoded pUS28 antagonizes CD4+ T cell recognition by targeting CIITA |
| title_full | The human cytomegalovirus-encoded pUS28 antagonizes CD4+ T cell recognition by targeting CIITA |
| title_fullStr | The human cytomegalovirus-encoded pUS28 antagonizes CD4+ T cell recognition by targeting CIITA |
| title_full_unstemmed | The human cytomegalovirus-encoded pUS28 antagonizes CD4+ T cell recognition by targeting CIITA |
| title_short | The human cytomegalovirus-encoded pUS28 antagonizes CD4+ T cell recognition by targeting CIITA |
| title_sort | human cytomegalovirus encoded pus28 antagonizes cd4 t cell recognition by targeting ciita |
| topic | Human cytomegalovirus HCMV human herpesvirus 5 HHV-5 US28 HLA class II |
| url | https://elifesciences.org/articles/96414 |
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