Control of CD8+ T cells through interference of Cytomegalovirus with the "peptide loading complex" (PLC)
Zusammenfassung der Projektergebnisse
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.
Projektbezogene Publikationen (Auswahl)
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(2007) Host immune system gene targeting by a viral miRNA. Science 317: 376-381
Stern-Ginossar N, Elefant N, Zimmermann A, Wolf DG, Saleh N, Biton M, Horwitz E, Prokocimer Z, Prichard M, Goldman-Wohl D, Greenfield C, Yagel S, Hengel H, Altuvia Y, Margalit H, Mandelboim O
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(2008) Human cytomegalovirus interferes with signal transducer and activator of transcription (STAT) 2 protein stability and tyrosine phosphorylation. Journal of General Virology 89: 2416-2426
Le VTK, Trilling M, Wilborn M, Hengel H, and Zimmermann A
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(2008) Mouse cytomegalovirus inhibits interferon-β gene expression and controls activation pathways of the interferon-β enhanceosome. Journal of General Virology 89: 1131-1141
Le VTK, Trilling M, Zimmermann A, Hengel H
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(2008) The dynamics of MCMV specific CD4 T cell responses during acute and latent infection. Journal of Immunology 181: 1128 -1134
Walton SM, Wyrsch P, Munks MW, Zimmermann A, Hengel H, Hill AB, and Oxenius A
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(2009) The non-structural 3/4A protease of HCV activates EGF-induced signal-transduction by cleavage of the T cell protein tyrosine phosphatase. Hepatology 49: 1810-1820
Brenndörfer ED, Karthe J, Frelin L, Cebula P, Erhardt A, Schulte am Esch J, Hengel H, Bartenschlager R, Sällberg M, Häussinger D, and Bode JG
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(2009): Gamma interferon-induced interferon regulatory factor 1-dependent antiviral response inhibits vaccinia virus replication in mouse but not human fibroblasts. In: Journal of virology 83 (8), S. 3684–3695
Trilling M, Le VTK, Zimmermann A, Ludwig H, Pfeffer K, Sutter G, Smith GL, and Hengel H
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(2010) Inhibition of mouse TAP by immune evasion molecules encoded by non-murine herpesviruses. Molecular Immunology 48: 835-845
Verweij MC, Knetsch W, Quinten E, Halenius A, van Bel N, Drijfhout JW, Ressing ME, Hengel H, van Hall T, Wiertz E
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(2011) Absence of crosspresenting cells in the salivary gland and viral immune evasion confine cytomegalovirus immune control to effector CD4 T cells. PLoS Pathogens, Aug;7(8): e1002214
Walton SM, Mandaric S, Torti N, Zimmermann A, Hengel H, and Oxenius A
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(2011) c-Src is required for complex formation between the hepatitis C virus encoded proteins NS5A and NS5B – a prerequisite for replication. Hepatology 53: 1127-1136
Pfannkuche A, Büther K, Karthe J, Poenisch M, Bartenschlager R, Trilling M, Hengel H, Willbold D, Häussinger D, and Bode JG
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(2011) Human cytomegalovirus disrupts the MHC class I peptide loading complex (PLC) and inhibits tapasin gene transcription. Journal of Virology 85: 3473-3485
Halenius A, Hauka S, Dölken L, Stindt J, Reinhardt H, Wiek C, Hanenberg H, Koszinowski UH, Momburg F, and Hengel H
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(2011) The cytomegaloviral protein pUL138 acts as potentiator of TNF receptor 1 surface density to enhance ULb’-encoded modulation of TNF-α signaling. Journal of Virology 85: 13260-13270
Le VTK, Trilling M, and Hengel H
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(2012) Decoding human cytomegalovirus. Science, 338: 1088-1093
Stern-Ginossar N, Weisburd B, Michalski A, Le VTK, Hein MY, Huang SX, Ma M, Shen B, Qian SB, Hengel H, Mann M, Ingolia NT, and Weissman JS
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(2012) Loss-of-function mutations within the IL-2 inducible kinase ITK in patients with EBV-associated lymphoproliferative diseases. Leukemia. 26(5): 963-971
Linka RM, Risse SL, Bienemann K, Werner M, Linka Y, Krux F, Synaeve C, Deenen R, Ginzel S, Dvorsky R, Gombert M, Halenius A, Hartig R, Helminen M, Fischer A, Stepensky P, Vettenranta K, Köhrer K, Ahmadian MR, Laws HJ, Fleckenstein B, Jumaa H, Latour S, Schraven B, Borkhardt A
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(2012) The efficiency of human cytomegalovirus pp65(495-503) CD8+ T cell epitope generation is determined by the balanced activities of cytosolic and endoplasmic reticulum-resident peptidases. Journal of Immumology 189: 529-538
Urban S, Textoris-Taube K, Reimann B, Janek K, Dannenberg T, Ebstein F, Seifert C, Zhao F, Kessler JH, Halenius A, Henklein P, Paschke J, Cadel S, Bernhard H, Ossendorp F, Foulon T, Schadendorf D, Paschen A, Seifert U
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(2013) A natural tapasin isoform lacking exon 3 modifies peptide loading complex function. European Journal of Immunology 43: 1459-69
Beutler N, Hauka S, Niepel A, Kowalewski DJ, Uhlmann J, Ghanem E, Erkelenz S, Wiek C, Hanenberg H, Schaal H, Stevanovic S, Springer S, Momburg F, Hengel H, and Halenius A
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(2014) Cytomegalovirus infection impairs immunosuppressive and antimicrobial effector functions of human multipotent mesenchymal stromal cells. Mediators of Inflammation
Meisel R, Heseler K, Nau J, Schmidt SK, Leineweber M, Pudelko S, Wenning J, Zimmermann A, Hengel H, Sinzger C, Degistirici Ö, Sorg RV, and Däubener W
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(2014) Human cytomegalovirus escapes antiviral activity by indoleamine-2,3-dioxygenase. Journal of General Virology, 95: 659-70
Zimmermann A, Hauka S, Maywald M, Schmidt SK, Däubener W, and Hengel H
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(2014) IL-12-producing monocytes and HLA-E control HCMV-driven NKG2C+ NK cell expansion. Journal of Clinical Investigation
Rölle A, Pollmann J, Ewen EM, Le VT, Halenius A, Hengel H, Cerwenka A
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(2014) “Activated” STAT proteins – a paradoxical consequence of inhibited JAK-STAT signalling in cytomegalovirus-infected cells. Journal of Immunology 192: 447-458
Trilling M, Le VTK, Rashidi-Alavijeh J, Katschinski B, Scheller J, Rose-John S, Androsiac GE, Jonjic S, Poli V, Pfeffer K, and Hengel H
