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Control of CD8+ T cells through interference of Cytomegalovirus with the "peptide loading complex" (PLC)

Subject Area Immunology
Term from 2007 to 2013
Project identifier Deutsche Forschungsgemeinschaft (DFG) - Project number 21644054
 
Final Report Year 2016

Final Report Abstract

Viral antigens are loaded onto MHC class I in the ER by the peptide loading complex (PLC) consisting of MHC class I, the peptide transporter TAP, and the chaperones tapasin, ERp57 and calreticulin. Tapasin brings MHC class I and TAP in close vicinity, and, together with the oxidoreductase ERp57 the peptide-receptive state of the MHC I is regulated. To cope with MHC class I antigen presentation HCMV encodes for several proteins utilizing post-translational escape strategies. While the primary goal of established HCMV stealth features is the quantitative downregulation of the bulk of MHC class I molecules from the cell surface, the targeting of the PLC is supposed to exert a qualitative influence. Deficiency of PLC function in HCMV-infected cells could alter the quality of HCMV-specific CD8+ T cell responses. Indeed, within the frame of this RU we have described an interruption of MHC class I recruitment to the PLC in HCMV infected cells. Next we found that deletion of US11 from HCMV restores recruitment of MHC-I to the PLC. Moreover, co-immunoprecipitation studies revealed binding of US11 to the PLC. It has been established that US11 mediates Derlin-1 dependent retrograde transport of MHC-I molecules from the ER to the cytosol for proteasomal degradation. Unexpectedly, wild-type US11 bound to HLA-B allotypes but inhibited their cell surface expression only modestly, whereas the HLA-A allotypes HLA-A*02:01 and -A*68:02 were efficiently degraded without reaching the cell surface. These observations raised the question whether US11 might disturb the quality control of HLA-B ligands. For clarification, the ligandome of HeLa cells (HLA-A*68:02/HLA-B*15:03) stably expressing US11Q192A (mutation prevents US11 association with Derlin-1, thereby disabling MHC-I degradation, but maintaining interaction with MHC-I) was analyzed. No effect on HLA-A*68:02 ligands was found, but the spectrum of HLA-B*15:03 typical ligands was significantly reduced compared to control cells, and, in addition, the usage of the P2 anchor residues was modified. Altogether, our data suggest that US11 is targeting HLA-A efficiently for degradation, whereas HLA-B are controlled by a novel immune evasive mechanism preventing the recruitment of MHC-I to the PLC, thereby interfering with proper peptide loading of HLA-B to escape CD8+ T cell recognition.

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