The human cytomegalovirus-encoded pUS28 antagonizes CD4+ T cell recognition by targeting CIITA

Area of Science:

• Immunology
• Virology
• Molecular Biology

Background:

• Human cytomegalovirus (HCMV) is an opportunistic pathogen that significantly impacts individuals with weakened immune systems.
• HCMV employs sophisticated mechanisms to evade host immune responses, including the suppression of human leukocyte antigen (HLA) expression.
• Specifically, HCMV interferes with the upregulation of HLA class II (HLA-II) molecules, such as HLA-DP and HLA-DR.

Purpose of the Study:

• To identify HCMV genes involved in antagonizing the expression of HLA class II molecules.
• To investigate the role of the latency regulator pUS28 in modulating the class II transactivator (CIITA)-driven expression of HLA-II.
• To elucidate the mechanism by which pUS28 inhibits HLA-II presentation and subsequent T cell recognition.

Main Methods:

• Screening of HCMV genes for interaction with the HLA class II-inducing transcription coordinator, CIITA.
• Co-expression assays to evaluate the effect of pUS28 on CIITA-mediated expression of HLA-II components (CD74, HLA-DR, HLA-DM, HLA-DQ, HLA-DP).
• Analysis of pUS28 mutants (wt-pUS28, R129A, C-terminus deletion) to determine the functional domains involved in CIITA antagonism.
• Assessment of CD4+ T cell responses to HCMV-infected cells with and without pUS28 expression.

Main Results:

• The latency regulator pUS28 was identified as a potent viral antagonist of CIITA-driven HLA-II expression.
• pUS28 significantly reduced CIITA protein abundance post-transcriptionally, affecting CD74, HLA-DR, HLA-DM, HLA-DQ, and HLA-DP.
• Both wild-type pUS28 and a G protein-coupled signaling-deficient mutant (R129A) inhibited HLA-II expression, while a C-terminal deletion mutant did not.
• pUS28 expression effectively blocked the induction of HLA-II and subsequent immune recognition by HCMV-specific CD4+ T cells.

Conclusions:

• HCMV utilizes the pUS28 protein to actively suppress HLA class II expression.
• pUS28 functions as a post-transcriptional antagonist of CIITA, thereby evading CD4+ T cell-mediated immune surveillance.
• This mechanism highlights a critical viral strategy for immune evasion, particularly relevant for HCMV persistence and pathogenesis in vulnerable populations.