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

Abstract

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.

Cancer Immunology: Immune Escape of Tumors—Expression and Regulation of HLA Class I Molecules and Its Role in Immunotherapies

“…The direct downregulation of HLA class I molecules and APM components is a major, frequent but diverse strategy of different viruses to escape from immune surveillance. 32,33 This is mediated, for example, by proteins, such as, for example, E3 19K in adenovirus or the immediate early immune checkpoint (ICP)47 of Herpes simplex virus, both capable of corrupting antigen presentation of respective virus-infected cells by blocking the TAP transporter or pulling HLA molecules away from the cell surface. 34 The unique short sequence 6 (US6) encoded by the human cytomegalovirus is an ER-resident type-I transmembrane glycoprotein with an active ER-luminal domain interacting with human TAP thereby inhibiting TAP by a distinct mechanism than ICP47.…”

“…In viral-driven malignancies, several viral factors have been shown to contribute to immune evasion of the infected host cells,30,31 but these processes are highly diverse. The direct downregulation of HLA class I molecules and APM components is a major, frequent but diverse strategy of different viruses to escape from immune surveillance 32,33. This is mediated, for example, by proteins, such as, for example, E3 19K in adenovirus or the immediate early immune checkpoint (ICP)47 of Herpes simplex virus, both capable of corrupting antigen presentation of respective virus-infected cells by blocking the TAP transporter or pulling HLA molecules away from the cell surface 34.…”

Semisynthetic Viral Inhibitor for Light Control of the MHC I Peptide Loading Complex

“…While a 54 aa synthetic photoconditional (pc‐)ICP47 2–55 allowed for spatiotemporal control of the PLC in vitro, [9] it cannot be used as a bait to isolate the native PLC from human cells for mechanistic and structural studies [10] . On the contrary, previous isolation strategies based on full‐length viral inhibitors irreversibly inactivated the purified PLC, prohibiting downstream activity assays [3, 10, 11] …”

“…[10] On the contrary, previous isolation strategies based on full-length viral inhibitors irreversibly inactivated the purified PLC, prohibiting downstream activity assays. [3,10,11] Here, we addressed this crucial aspect by engineering a full-length ICP47 with a C-terminal flexible glycine-serine linker and a streptavidin-binding peptide (SBP) tag for affinity purification. Linker and affinity tag increase the solubility of the hydrophobic full-length ICP47, leading to an overall length of 140 aa for pc-ICP47 SBP .…”

Semisynthetic Viral Inhibitor for Light Control of the MHC I Peptide Loading Complex

“… [10] On the contrary, previous isolation strategies based on full‐length viral inhibitors irreversibly inactivated the purified PLC, prohibiting downstream activity assays. [ 3 , 10 , 11 ]…”