Journal Article

DKFZ-2025-01353

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png The human cytomegalovirus-encoded pUS28 antagonizes CD4+ T cell recognition by targeting CIITA.

Maassen, F. ; Le-Trilling, V. T. K. ; Betke, L. ; Bracht, T. ; Siegmund, C. ; Bayer, M. ; Katschinski, B. ; Belter, A. ; Becker, T. ; Mennerich, D. ; Voigt, S. ; Frappier, L. ; Sitek, B. ; Fleischhauer, K.DKFZ* ; Trilling, M.

2025
eLife Sciences Publications Cambridge

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Please use a persistent id in citations: doi:10.7554/eLife.96414

Abstract: 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.

Keyword(s): Humans (MeSH) ; Trans-Activators: metabolism (MeSH) ; Trans-Activators: antagonists & inhibitors (MeSH) ; Trans-Activators: genetics (MeSH) ; Cytomegalovirus: genetics (MeSH) ; Cytomegalovirus: immunology (MeSH) ; CD4-Positive T-Lymphocytes: immunology (MeSH) ; Nuclear Proteins: metabolism (MeSH) ; Nuclear Proteins: antagonists & inhibitors (MeSH) ; Nuclear Proteins: genetics (MeSH) ; Viral Proteins: metabolism (MeSH) ; Viral Proteins: genetics (MeSH) ; Host-Pathogen Interactions (MeSH) ; CD4+ T cells ; CD74 ; CIITA ; G protein-coupled receptor ; GPCR ; HCMV ; HHV-5 ; HLA class II ; HLA-DP ; HLA-DR ; Human cytomegalovirus ; M33 ; US28 ; human herpesvirus 5 ; infectious disease ; latency ; microbiology ; viruses ; Trans-Activators ; MHC class II transactivator protein ; Nuclear Proteins ; Viral Proteins

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Contributing Institute(s):

1. DKTK Koordinierungsstelle Essen/Düsseldorf (ED01)

Research Program(s):

1. 899 - ohne Topic (POF4-899) (POF4-899)

Appears in the scientific report 2025

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