Viral immune evasins impact antigen presentation by allele-specific trapping of MHC I at the peptide-loading complex

• Published in: Scientific reports Vol. 12; no. 1; pp. 1516 - 11
• Main Authors: Sethumadhavan, Sunesh, Barth, Marie, Spaapen, Robbert M., Schmidt, Carla, Trowitzsch, Simon, Tampé, Robert
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 27.01.2022; Nature Publishing Group; Nature Portfolio
• Subjects: 631/1647; 631/1647/2230; 631/1647/296; 631/250; 631/250/21; 631/250/2161; 631/45; 631/45/881; 631/80; Alleles; Allotypes; Antigen presentation; Antigen Presentation - immunology; Antigen processing; Cytotoxicity; Herpes simplex; Histocompatibility antigen HLA; Histocompatibility Antigens Class I - genetics; Histocompatibility Antigens Class I - immunology; Histocompatibility Antigens Class I - metabolism; Humanities and Social Sciences; Humans; Immediate-Early Proteins - genetics; Immediate-Early Proteins - immunology; Immediate-Early Proteins - metabolism; Lymphocytes T; Major histocompatibility complex; multidisciplinary; Peptides; Peptides - immunology; Science; Science (multidisciplinary); TAP protein; Viral Proteins - genetics; Viral Proteins - immunology; Viral Proteins - metabolism
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-022-05000-9

Major histocompatibility complex class I (MHC I) molecules present antigenic peptides to cytotoxic T cells to eliminate infected or cancerous cells. The transporter associated with antigen processing (TAP) shuttles proteasomally generated peptides into the ER for MHC I loading. As central part of the peptide-loading complex (PLC), TAP is targeted by viral factors, which inhibit peptide supply and thereby impact MHC I-mediated immune responses. However, it is still poorly understood how antigen presentation via different MHC I allotypes is affected by TAP inhibition. Here, we show that conditional expression of herpes simplex viral ICP47 suppresses surface presentation of HLA-A and HLA-C, but not of HLA-B, while the human cytomegaloviral US6 reduces surface levels of all MHC I allotypes. This marked difference in HLA-B antigen presentation is echoed by an enrichment of HLA-B allomorphs at US6-arrested PLC in comparison to ICP47-PLC. Although both viral factors prevent TAP-mediated peptide supply, our data imply that MHC I allomorphs favor different conformationally arrested states of the PLC, leading to differential downregulation of MHC I surface presentation. These findings will help understand MHC I biology in general and will even advance the targeted treatment of infections depending on patients’ allotypes.