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.
Highlights
Major histocompatibility complex class I (MHC I)-mediated presentation of antigenic peptides to cytotoxic T-lymphocytes (CTLs) is fundamental in mounting an immune response against virally infected or malignantly transformed cells[1,2]
We did not observe a substantial variation in the overall expression of TAP1 and different MHC I allomorphs in either Raji (HLA-A*03:01, HLA-B*15:10, and HLA-C*04:01) (Fig. 1c) or Mel JuSo cells (HLA-A*01:01, HLA-B*08:01, and HLA-Cw7) (Supplementary Fig. 1c), demonstrating that the protein expression levels of central components of the antigen presentation pathway are not altered upon expression of ICP47 or unique short sequence 6 (US6)
Since no global effect on the MHC I expression level was observed in cell lysates in which ICP47- and US6expressing cells were compared with non-induced cells (Fig. 1c), we rationalized that preferential trapping of MHC I in the ICP47- or US6-arrested peptide-loading complex (PLC) was the reason for the different surface levels of HLA allomorphs
Summary
Major histocompatibility complex class I (MHC I)-mediated presentation of antigenic peptides to cytotoxic T-lymphocytes (CTLs) is fundamental in mounting an immune response against virally infected or malignantly transformed cells[1,2]. Stable peptide-MHC I (pMHC I) complexes can exit the ER and travel via the secretory pathway to the cell surface where they present their antigenic cargo to CTLs. MHC I molecules are broadly classified into classical (HLA-A, HLA-B, and HLAC) and non-classical alleles (HLA-E, HLA-F, HLA-G, MR1, and CD1), both of which regulate and modulate the immune response in different ways, especially during chronic viral infections[11,12,13,14,15,16]. Common to all TAP inhibitors is that they arrest the transporter in a transport-incompetent state, thereby blocking peptide supply to the ER lumen This shortage of peptides, in turn, leads to a reduction of peptide-loaded MHC I molecules on the cell surface and helps the virus escape the host immune r esponse[17,20,21,30]. Our results reveal a molecular mechanism behind allele-specific blockage of MHC I antigen presentation and provide opportunities for the development of new treatments for infectious diseases
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