Publications (29)284.61 Total impact
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Dataset: Suppl. Data
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Article: Circumventing tolerance to a human MDM2-derived tumor antigen by TCR gene transfer.
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ABSTRACT: We identified a tumor-associated cytotoxic T lymphocyte (CTL) epitope derived from the widely expressed human MDM2 oncoprotein and were able to bypass self-tolerance to this tumor antigen in HLA-A*0201 (A2.1) transgenic mice and by generating A2.1-negative, allo-A2.1-restricted human T lymphocytes. A broad range of malignant, as opposed to nontransformed cells, were killed by high-avidity transgenic mouse and allogeneic human CTLs specific for the A2.1-presented MDM2 epitope. Whereas the self-A2.1-restricted human T cell repertoire gave rise only to low-avidity CTLs unable to recognize the natural MDM2 peptide, human A2.1+ T lymphocytes were turned into efficient MDM2-specific CTLs upon expression of wild-type and partially humanized high-affinity T cell antigen receptor (TCR) genes derived from the transgenic mice. These results demonstrate that TCR gene transfer can be used to circumvent self-tolerance of autologous T lymphocytes to universal tumor antigens and thus provide the basis for a TCR gene transfer-based broad-spectrum immunotherapy of malignant disease.Nature Immunology 11/2001; 2(10):962-70. · 26.01 Impact Factor -
Article: The murine cytomegalovirus pp89 immunodominant H-2Ld epitope is generated and translocated into the endoplasmic reticulum as an 11-mer precursor peptide.
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ABSTRACT: The 20S proteasome is involved in the processing of MHC class I-presented Ags. A number of epitopes is known to be generated as precursor peptides requiring trimming either before or after translocation into the endoplasmic reticulum (ER). In this study, we have followed the proteasomal processing and TAP-dependent ER translocation of the immunodominant epitope of the murine CMV immediate early protein pp89. For the first time, we experimentally linked peptide generation by the proteasome system and TAP-dependent ER translocation. Our experiments show that the proteasome generates both an N-terminally extended 11-mer precursor peptide as well as the correct H2-L(d) 9-mer epitope, a process that is accelerated in the presence of PA28. Our direct peptide translocation assays, however, demonstrate that only the 11-mer precursor peptide is transported into the ER by TAPs, whereas the epitope itself is not translocated. In consequence, our combined proteasome/TAP assays show that the 11-mer precursor is the immunorelevant peptide product that requires N-terminal trimming in the ER for MHC class I binding.The Journal of Immunology 09/2001; 167(3):1515-21. · 5.79 Impact Factor -
Article: Different proteasome subtypes in a single tissue exhibit different enzymatic properties.
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ABSTRACT: It is concluded from many experiments that mammalian tissues and cells must contain a heterogeneous population of 20 S proteasome complexes. We describe the purification and separation by chromatographic procedures of constitutive 20 S proteasomes, 20 S immuno-proteasomes and intermediate-type 20 S proteasomes from a given tissue. Our data demonstrate that each of these three groups comprises more than one subtype and that the relative ratios of the subtypes differ between different rat tissues. Thus, six subtypes could be identified in rat muscle tissue. Subtypes I and II are constitutive proteasomes, while subtypes V and VI comprise immuno-proteasomes. Subtypes III and IV belong to a group of intermediate-type proteasomes. The subtypes differ with regard to their enzymatic characteristics. Subtypes I-III exhibit high chymotrypsin-like activity and high peptidylglutamylpeptide hydrolysing activity, while these activities are depressed in subtypes IV-VI. In contrast, trypsin-like activity of subtypes IV-VI is enhanced in comparison to subtypes I-III. Importantly, the subtypes also differ in their preferential cleavage site usage when tested by digestion of a synthetic 25mer polypeptide substrate. Therefore, the characteristics of proteasomes purified from tissues or cells represent the average of the different subtype activities which in turn may have different functions in vivo.Journal of Molecular Biology 12/2000; 303(5):643-53. · 4.00 Impact Factor -
Article: Macrophages escape inhibition of major histocompatibility complex class I-dependent antigen presentation by cytomegalovirus.
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ABSTRACT: The mouse cytomegalovirus (MCMV) m152- and m06-encoded glycoproteins gp40 and gp48, respectively, independently downregulate major histocompatibility complex (MHC) class I surface expression during the course of productive MCMV infection in fibroblasts. As a result, presentation of an immediate-early protein pp89-derived nonapeptide to H-2L(d)-restricted CD8(+) cytotoxic T cells is completely prevented in fibroblasts. Here we demonstrate that MCMV-infected primary bone marrow macrophages and the macrophage cell line J774 constitutively present pp89 peptides during permissive MCMV infection to cytotoxic T lymphocytes (CTL). In contrast to fibroblasts, expression of the m152 and m06 genes in macrophages does not affect surface expression of MHC class I. Assessment of pp89 synthesis and quantification of extracted peptide revealed a significantly higher efficiency of macrophages than of fibroblasts to process pp89 into finally trimmed peptide. The yield of pp89 peptide determined in MCMV-infected tissues of bone marrow chimeras confirmed that bone marrow-derived cells represent a prime source of pp89 processing in parenchymal organs. The finding that macrophages resist the viral control of MHC I-dependent antigen presentation reconciles the paradox of efficient induction of CMV-specific CD8(+) CTL in vivo despite extensive potential of CMVs to subvert MHC class I.Journal of Virology 10/2000; 74(17):7861-8. · 5.40 Impact Factor -
Article: MHC class I antigen processing of an adenovirus CTL epitope is linked to the levels of immunoproteasomes in infected cells.
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ABSTRACT: Proteasomes are the major source for the generation of peptides bound by MHC class I molecules. To study the functional relevance of the IFN-gamma-inducible proteasome subunits low molecular mass protein 2 (LMP2), LMP7, and mouse embryonal cell (MEC) ligand 1 in Ag processing and concomitantly that of immunoproteasomes, we established the tetracycline-regulated mouse cell line MEC217, allowing the titrable formation of immunoproteasomes. Infection of MEC217 cells with Adenovirus type 5 (Ad5) and analysis of Ag presentation with Ad5-specific CTL showed that cells containing immunoproteasomes processed the viral early 1B protein (E1B)-derived epitope E1B192-200 with increased efficiency, thus allowing a faster detection of viral entry in induced cells. Importantly, optimal CTL activation was already achieved at submaximal immunosubunit expression. In contrast, digestion of E1B-polypeptide with purified proteasomes in vitro yielded E1B192-200 at quantities that were proportional to the relative contents of immunosubunits. Our data provide evidence that the IFN-gamma-inducible proteasome subunits, when present at relatively low levels as at initial stages of infection, already increase the efficiency of antigenic peptide generation and thereby enhance MHC class I Ag processing in infected cells.The Journal of Immunology 06/2000; 164(9):4500-6. · 5.79 Impact Factor -
Article: Efficient generation of a hepatitis B virus cytotoxic T lymphocyte epitope requires the structural features of immunoproteasomes.
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ABSTRACT: Interferon (IFN)-gamma-induced cells express the proteasome subunits low molecular weight protein (LMP)2, LMP7, and MECL-1 (multicatalytic endopeptidase complex-like 1), leading to the formation of immunoproteasomes. Although these subunits are thought to optimize MHC class I antigen processing, the extent of their role and the mechanistic aspects involved remain unclear. Herein, we study the proteolytic generation of an human histocompatibility leukocyte antigen (HLA)-Aw68-restricted hepatitis B virus core antigen (HBcAg) cytotoxic T lymphocyte (CTL) epitope that is recognized by peripheral blood lymphocytes from patients with acute self-limited but not chronic hepatitis B virus (HBV). Immunological data suggest that IFN-gamma-induced rather than uninduced HeLa cells process and present the HBV CTL epitope upon infection with HBcAg-expressing vaccinia viruses. Analyses of 20S proteasome digests of synthetic polypeptides covering the antigenic HBcAg peptide demonstrate that only immunoproteasomes efficiently perform the cleavages needed for the liberation of this HBV CTL epitope. Although the concerted presence of the three immunosubunits appears essential, we find that both catalytically active LMP7 and inactive LMP7 T1A support CTL epitope generation. We conclude that LMP7 influences the structural features of 20S proteasomes, thereby enhancing the activity of the LMP2 and MECL-1 catalytic sites, which provide cleavage specificity. Thus, LMP7 incorporation is of greater functional importance for the generation of an HBV CTL epitope than cleavage specificity.Journal of Experimental Medicine 03/2000; 191(3):503-14. · 13.85 Impact Factor -
Article: Autoxidation of amyloid precursor protein and formation of reactive oxygen species.
Advances in experimental medicine and biology 02/1999; 448:183-92. · 1.09 Impact Factor -
Article: The sequence alteration associated with a mutational hotspot in p53 protects cells from lysis by cytotoxic T lymphocytes specific for a flanking peptide epitope.
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ABSTRACT: A high proportion of tumors arise due to mutation of the p53 tumor suppressor protein. A p53 hotspot mutation at amino acid position 273 from R to H, flanking a peptide epitope that spans residues 264-272, renders cells resistant to killing by human histocompatibility leukocyte antigen (HLA)-A*0201-restricted cytotoxic T lymphocytes (CTLs) specific for this epitope. Acquisition of the R to H mutation at residue 273 of the human p53 protein promotes tumor growth in vivo by selective escape from recognition by p53.264-272 peptide-specific CTLs. Synthetic 27-mer p53 polypeptides covering the antigenic nonamer region 264-272 of p53 were used as proteasome substrates to investigate whether the R to H mutation at the P1' position of the COOH terminus of the epitope affects proteasome-mediated processing of the protein. Analysis of the generated products by tandem mass spectrometry and the kinetics of polypeptide processing in conjunction with CTL assays demonstrate that the R to H mutation alters proteasomal processing of the p53 protein by inhibiting proteolytic cleavage between residues 272 and 273. This prevents the release of the natural CTL epitope that spans flanking residues 264-272 as well as a putative precursor peptide. These results demonstrate that mutation of p53 not only leads to malignant transformation but may also, in some instances, affect immune surveillance and should be considered in the design of cancer vaccines.Journal of Experimental Medicine 10/1998; 188(6):1017-28. · 13.85 Impact Factor -
Article: The making of the dominant MHC class I ligand SYFPEITHI.
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ABSTRACT: The proteasome contributes to the generation of most of the peptide ligands of MHC class I molecules. To compare the identity of the peptides generated by the proteasome with those finally presented by MHC class I molecules, we generated a monoclonal antibody recognizing the C-terminal part of the dominant H2-Kd ligand SYFPEITHI derived from the JAK1 tyrosine kinase. Immunoprecipitations of lysates from H2-Kd-expressing or non-expressing cells revealed that only in the presence of H2-Kd SYFPEITHI could be isolated. No longer potential precursor peptide containing SYFPEITHI could be detected. Surprisingly, a peptide lacking the first two amino acids, FPEITHI, was isolated independently of the presence of H2-Kd molecules. The detection of only SYFPEITHI and FPEITHI in cell lysates corresponded with the strong generation of these two peptides in in vitro digests of elongated SYFPEITHI-containing peptides with purified 20S proteasomes. Our results indicate that MHC ligands can be generated directly by the proteasome in vivo and that at least for SYFPEITHI the expression of the corresponding MHC molecule is critical for protection of the ligand in vivo.European Journal of Immunology 09/1998; 28(8):2478-86. · 5.10 Impact Factor -
Article: Copper-binding amyloid precursor protein undergoes a site-specific fragmentation in the reduction of hydrogen peroxide.
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ABSTRACT: The extracellular domain of transmembrane Abeta amyloid precursor protein (APP) has a Cu(II) reducing activity upon Cu(II) binding associated with the formation of a new disulfide bridge. The complete assignment of the disulfide bond revealed the involvement of cysteines 144 and 158 around copper-binding histidine residues. The vulnerability of APP-Cu(I) complexes to reactive oxygen species was elaborated as a site-specific and random fragmentation of APP in a time-dependent manner and at low concentrations of H2O2. Analysis of the specific reaction revealed the generation of C-terminal polypeptides, containing the Abeta domain. APP catalyzed the reduction of H2O2 and oxidation of Cu(I) to Cu(II) in a "peroxidative" reaction in vitro. The resulting bound copper-hydroxyl radical intermediate [APP-Cu(II)(.OH)] then likely participated in a Fenton type of reaction with radical formation as a prerequisite for protein degradation. Evidence from two observations suggests that the reaction takes place in two phases. Bathocuproine, a trapping agent for Cu(I), abolished the initial fragmentation, and chelation of Cu(II) by DTPA (diethylenetriaminepentaacetic acid) interrupted the reaction cascade induced by H2O2 at later stages. Consequently, the results suggest that a cytotoxic gain-of-function of APP-Cu(I) complexes might result in a perturbation of free radical homeostasis. What significance such a perturbation may have for the pathogenesis of Alzheimer's disease remains to be determined.Biochemistry 06/1998; 37(20):7224-30. · 3.42 Impact Factor -
Article: Inactivation of a defined active site in the mouse 20S proteasome complex enhances major histocompatibility complex class I antigen presentation of a murine cytomegalovirus protein.
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ABSTRACT: Proteasomes generate peptides bound by major histocompatibility complex (MHC) class I molecules. Avoiding proteasome inhibitors, which in most cases do not distinguish between individual active sites within the cell, we used a molecular genetic approach that allowed for the first time the in vivo analysis of defined proteasomal active sites with regard to their significance for antigen processing. Functional elimination of the delta/low molecular weight protein (LMP) 2 sites by substitution with a mutated inactive LMP2 T1A subunit results in reduced cell surface expression of the MHC class I H-2Ld and H-2Dd molecules. Surface levels of H-2Ld and H-2Dd molecules were restored by external loading with peptides. However, as a result of the active site mutation, MHC class I presentation of a 9-mer peptide derived from a protein of murine cytomegalovirus was enhanced about three- to fivefold. Our experiments provide evidence that the delta/LMP2 active site elimination limits the processing and presentation of several peptides, but may be, nonetheless, beneficial for the generation and presentation of others.Journal of Experimental Medicine 06/1998; 187(10):1641-6. · 13.85 Impact Factor -
Article: IFN-gamma is a prerequisite for optimal antigen processing of viral peptides in vivo.
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ABSTRACT: The immediate early protein pp89 of mouse CMV is processed into the nonapeptide YPHFMPTNL, which is presented to CD8+ T lymphocytes by the H-2 Ld molecule. The tissue distribution of this peptide was determined during the course of mouse CMV infection. In tissues, there was no general correlation between peptide processing and infectious virus productivity. Immunosuppression by sublethal irradiation resulted in enhanced MCMV replication but did not increase the peptide yield and drastically reduced the peptide to plaque-forming unit rate in infected organs. IFN-gamma administration restored efficient peptide processing in the immunocompromised host, and neutralization of IFN-gamma in the immunocompetent host decreased peptide processing. This suggests that the efficiency of peptide processing after CMV infection in vivo is governed by IFN-gamma rather than by the productivity of virus infection.The Journal of Immunology 05/1997; 158(7):3303-10. · 5.79 Impact Factor -
Article: A single residue exchange within a viral CTL epitope alters proteasome-mediated degradation resulting in lack of antigen presentation.
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ABSTRACT: CTL epitope (KSPWFTTL) encoded by AKV/MCF type of murine leukemia virus (MuLV) differs from the sequence in Friend/Moloney/Rauscher (FMR) type in one residue (RSPWFTTL). CTL experiments indicated defective processing of the FMR peptide in tumor cells. Proteasome-mediated digestion of AKV/MCF-type 26-mer peptides resulted in the early generation and higher levels of epitope-containing fragments than digestion of FMR-type peptides, explained by prominent cleavage next to R in the FMR sequence. The fragments were identified as 10- and 11-mer peptides and were efficiently translocated by TAP. The naturally presented AKV/MCF peptide is the 8-mer, indicating ER peptide trimming. In conclusion, a single residue exchange can cause CTL epitope destruction by specific proteasomal cleavage.Immunity 09/1996; 5(2):115-24. · 21.64 Impact Factor -
Article: Coordinated dual cleavages induced by the proteasome regulator PA28 lead to dominant MHC ligands.
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ABSTRACT: The eukaryotic 20S proteasome is known to associate with the IFN gamma-inducible regulator PA28. We analyzed the kinetics of product generation by 20S proteasomes with and without PA28. In the absence of PA28, the 20S proteasome rapidly generates peptides that have been cleaved only once, while internal fragments accumulate only slowly. In the presence of PA28, products generated by two flanking cleavages appear immediately as main products while the generation of single-cleavage products is strongly reduced. Kinetic data support a PA28-induced, coordinated double-cleavage mechanism. In particular, degradation of peptides derived from mouse cytomegalovirus pp89 and JAK1 kinase in the presence of PA28 leads to strongly enhanced production of the respective major histocompatibility complex ligands and potential precursors. These results show that PA28 profoundly alters the cleavage mechanism of the proteasome and appears to optimize the generation of dominant T-cell epitopes.Cell 08/1996; 86(2):253-62. · 32.40 Impact Factor -
Article: The amyloid precursor protein of Alzheimer's disease in the reduction of copper(II) to copper(I)
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ABSTRACT: The transition metal ion copper(II) has a critical role in chronic neurologic diseases. The amyloid precursor protein (APP) of Alzheimer's disease or a synthetic peptide representing its copper-binding site reduced bound copper(II) to copper(I). This copper ion-mediated redox reaction led to disulfide bond formation in APP, which indicated that free sulfhydryl groups of APP were involved. Neither superoxide nor hydrogen peroxide had an effect on the kinetics of copper(II) reduction. The reduction of copper(II) to copper(I) by APP involves an electron-transfer reaction and could enhance the production of hydroxyl radicals, which could then attack nearby sites. Thus, copper-mediated toxicity may contribute to neurodegeneration in Alzheimer's disease.Science 04/1996; 271(5254):1406-9. · 31.20 Impact Factor -
Article: The cleavage preference of the proteasome governs the yield of antigenic peptides.
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ABSTRACT: Proteasomes degrade endogenous proteins in the cytosol. The potential contribution of the proteasome to the effect of flanking sequences on the presentation of an antigenic epitope presented by the major histocompatibility complex class I allele Ld was studied. Peptides generated in cells from minigenes coding for peptides of 17- and 19-amino acid length were compared with the in vitro 20S proteasome degradation products of the respective synthetic peptides. The quality of generated peptides was independent of ubiquitination. In vivo and in vitro processing products were indistinguishable with respect to peptide size and abundance. Altering the neighboring sequence substantially improved the yield of the final antigenic nonapeptide by 20S proteasome cleavage. These results suggest that, in addition to the presence of major histocompatibility complex class I allelic motifs, the cleavage preference of the proteasome can define the antigenic potential of a protein.Journal of Experimental Medicine 01/1996; 182(6):1865-70. · 13.85 Impact Factor -
Article: The interferon-gamma-inducible 11 S regulator (PA28) and the LMP2/LMP7 subunits govern the peptide production by the 20 S proteasome in vitro.
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ABSTRACT: Antigenic peptides presented on major histocompatibility complex (MHC) class I molecules to cytotoxic T cells are generated in the cytosol by the 20 S proteasome. Upon stimulation of antigen presenting cells with interferon-gamma, two constitutive subunits of the 20 S proteasome are replaced by the MHC-encoded subunits low molecular mass polypeptide (LMP) 2 and LMP 7. In addition the expression of the two subunits of the 11 S regulator of the 20 S proteasome (PA28) are increased. As the function of LMP2 and LMP7 in antigen presentation is still controversial, we tested whether these subunits might operate by modifying proteasome activation through the 11 S regulator. We strongly overexpressed the two LMP subunits separately or together by transfection in murine fibroblasts. Isolated 20 S proteasomes from LMP transfectants were applied in digests of a 25-mer peptide in the presence or absence of a purified preparation of 11 S regulator from rabbit erythrocytes. Analysis of the cleavage products by high performance liquid chromatography and electrospray mass spectroscopy revealed marked differences in the peptide product profile in dependence on the LMP2 and LMP7 content. While the 11 S regulator did not preferentially activate LMP2 or 7 containing proteasomes, the binding of the 11 S regulator to any of the proteasome preparations markedly changed both the quality and quantity of peptides produced. These results suggest that the 11 S regulator increases the spectrum of peptides which can be generated in antigen presenting cells.Journal of Biological Chemistry 11/1995; 270(40):23808-15. · 4.77 Impact Factor -
Article: Elongated peptides, not the predicted nonapeptide stimulate a major histocompatibility complex class I-restricted cytotoxic T lymphocyte clone with specificity for a bacterial heat shock protein.
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ABSTRACT: The peptides recognized by an H-2Db-restricted CD8 cytotoxic T lymphocyte (CTL) clone which is specific for the 60-kDa mycobacterial heat shock protein (hsp) and cross-reacts with stressed host cells were characterized. None of the nonapeptides from hsp60 conforming to the H-2Db binding motif were able to sensitize target cells for lysis by this CTL clone. Sequence analysis of the stimulatory fraction from a trypsin digest of hsp60, together with synthetic peptide studies, defined a cluster of overlapping epitopes. Carboxy-terminal extension by at least one amino acid of the nonamer predicted to bind best to H-2Db was essential for CTL recognition. Two such elongated peptides, a 10-mer and a 12-mer stimulated the clone at similarly low concentrations in the 100 pM range. We assume that these two peptides comply best with the natural epitope. In contrast, the 11-mer was inactive. The stimulatory 10-mer bound to H-2Db with an efficacy similar to that of the nonapeptide corresponding to the H-2Db motif, as revealed by peptide induced major histocompatibility complex (MHC) surface expression on RMA-S cells and competitive blocking of epitope recognition by the nonamer. Binding of these carboxy-terminally extended peptides to the MHC groove can be explained by anchoring through the amino acid residue Asn in position 5 of the peptide and by intrusion of the hydrophobic carboxy-terminal Ala (10-mer) or Leu (12-mer), but not Gly (11-mer), into the hydrophobic pocket of the H-2Db cleft. Because the carboxy-terminal part is thus larger than predicted, this region of the peptide may arch up from the binding groove. We assume that recognition of steric components of the MHC/peptide complex broaden the range of epitope specificity for a single T cell receptor. This flexibility not only promotes recognition of several overlapping peptides from a single antigen, but may also increase the chance of cross-reaction with similar peptides from unrelated proteins, including autoantigens. Consistent with this latter assumption, the T cell clone cross-recognizes mycobacterial hsp60 and stressed host cells.European Journal of Immunology 01/1995; 24(12):3161-9. · 5.10 Impact Factor -
Article: Interferon gamma stimulation modulates the proteolytic activity and cleavage site preference of 20S mouse proteasomes.
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ABSTRACT: The proteasome is a 700-kD multisubunit enzyme complex with several proteolytically active sites. The enzyme complex is involved in both ubiquitin-dependent and -independent protein degradation and may contribute to the processing of antigens presented by major histocompatibility complex (MHC) class I molecules. Here we demonstrate that treatment of mouse fibroblast cells with 20 U interferon gamma (IFN-gamma) for 3 d induces a change in the proteasome subunit composition and that the beta-type subunit LMP2, which is encoded in the MHC class II region, is incorporated into the enzyme complex. This is paralleled by reduction of the homologous delta-subunit. IFN-gamma stimulation results in a downregulation of the chymotrypsin-like Suc-LLVY-MCA peptide hydrolyzing activity of 20S proteasomes whereas the trypsin-like activity remains unaffected. When tested as a substrate a synthetic 25-mer polypeptide whose sequence covers the antigenic nonapeptide YPHFMPTNL of the MCMV pp89, 20S proteasomes of IFN-gamma-induced cells exhibit altered chymotrypsin-like cleavage site preferences. In the absence of IFN-gamma induction, the naturally processed nonamer peptide that is presented by MHC class I molecules appears as a minor cleavage product. IFN-gamma activation does not result in an increase of the final peptide but results in a different set of peptides. We hypothesize that these peptides represent precursor peptides that can be trimmed to final peptide size.Journal of Experimental Medicine 04/1994; 179(3):901-9. · 13.85 Impact Factor
Top co-authors
Top Journals
Institutions
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1995–2001
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Humboldt-Universität zu Berlin
- Department of Chemistry
Berlin, Land Berlin, Germany
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2000
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Deutsches Diabetes-Zentrum
Düsseldorf, North Rhine-Westphalia, Germany
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1998–2000
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Ludwig-Maximilian-University of Munich
München, Bavaria, Germany
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1997–2000
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Max von Pettenkofer-Institut
München, Bavaria, Germany
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1994–1999
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Universität Heidelberg
- Center for Molecular Biology (ZMBH)
Heidelberg, Baden-Wuerttemberg, Germany -
University of Rijeka
- Faculty of Medicine
Rijeka, Primorsko-Goranska Zupanija, Croatia
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1991–1992
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Universität Ulm
- Institute of Microbiology and Biotechnology
Ulm, Baden-Wuerttemberg, Germany
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