TY  - JOUR
AU  - Maassen, Fabienne
AU  - Le-Trilling, Vu Thuy Khanh
AU  - Betke, Luisa
AU  - Bracht, Thilo
AU  - Siegmund, Corinna
AU  - Bayer, Malte
AU  - Katschinski, Benjamin
AU  - Belter, Antonia
AU  - Becker, Tanja
AU  - Mennerich, Denise
AU  - Voigt, Sebastian
AU  - Frappier, Lori
AU  - Sitek, Barbara
AU  - Fleischhauer, Katharina
AU  - Trilling, Mirko
TI  - The human cytomegalovirus-encoded pUS28 antagonizes CD4+ T cell recognition by targeting CIITA.
JO  - eLife
VL  - 14
SN  - 2050-084X
CY  - Cambridge
PB  - eLife Sciences Publications
M1  - DKFZ-2025-01353
SP  - e96414
PY  - 2025
AB  - 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.
KW  - Humans
KW  - Trans-Activators: metabolism
KW  - Trans-Activators: antagonists & inhibitors
KW  - Trans-Activators: genetics
KW  - Cytomegalovirus: genetics
KW  - Cytomegalovirus: immunology
KW  - CD4-Positive T-Lymphocytes: immunology
KW  - Nuclear Proteins: metabolism
KW  - Nuclear Proteins: antagonists & inhibitors
KW  - Nuclear Proteins: genetics
KW  - Viral Proteins: metabolism
KW  - Viral Proteins: genetics
KW  - Host-Pathogen Interactions
KW  - CD4+ T cells (Other)
KW  - CD74 (Other)
KW  - CIITA (Other)
KW  - G protein-coupled receptor (Other)
KW  - GPCR (Other)
KW  - HCMV (Other)
KW  - HHV-5 (Other)
KW  - HLA class II (Other)
KW  - HLA-DP (Other)
KW  - HLA-DR (Other)
KW  - Human cytomegalovirus (Other)
KW  - M33 (Other)
KW  - US28 (Other)
KW  - human herpesvirus 5 (Other)
KW  - infectious disease (Other)
KW  - latency (Other)
KW  - microbiology (Other)
KW  - viruses (Other)
KW  - Trans-Activators (NLM Chemicals)
KW  - MHC class II transactivator protein (NLM Chemicals)
KW  - Nuclear Proteins (NLM Chemicals)
KW  - Viral Proteins (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:40608405
C2  - pmc:PMC12226020
DO  - DOI:10.7554/eLife.96414
UR  - https://inrepo02.dkfz.de/record/302813
ER  -