Search PubMed⌕ Search

Biomedical subjects

Peter van Endert

Publications and source records attributed to Peter van Endert.

8 recordsLinked to original sources
PubMed2006

Calreticulin exposure dictates the immunogenicity of cancer cell death.

Anthracyclin-treated tumor cells are particularly effective in eliciting an anticancer immune response, whereas other DNA-damaging agents such as etoposide and mitomycin C do not induce immunogenic cell death. Here we show that anthracyclins induce the rapid, preapoptotic translocation of calreticulin (CRT) to the cell surface. Blockade or knockdown of CRT suppressed the phagocytosis of anthracyclin-treated tumor cells by dendritic cells and abolished their immunogenicity in mice. The anthracyclin-induced CRT translocation was mimicked by inhibition of the protein phosphatase 1/GADD34 complex. Administration of recombinant CRT or inhibitors of protein phosphatase 1/GADD34 restored the immunogenicity of cell death elicited by etoposide and mitomycin C, and enhanced their antitumor effects in vivo. These data identify CRT as a key feature determining anticancer immune responses and delineate a possible strategy for immunogenic chemotherapy.

Animals↗
PubMed2006

HLA class I epitope discovery in type 1 diabetes.

Type 1 diabetes mellitus (T1DM) results from the destruction of beta cells by autoantigen-specific T cells. In the non-obese diabetic (NOD) mouse model, CD8+ T cells play an essential role in both the initial triggering of insulitis and its destructive phase, and proinsulin (PI) is one of the dominant target antigens (Ags). However, little is known about the beta cell epitopes presented by HLA class I molecules and recognized by human CD8+ T cells. We and other groups recently applied reverse immunology approaches to identify HLA class I-restricted PI epitopes. To establish an inventory of potential naturally processed epitopes, whole human PI or the transitional region between the B-chain and C-peptide were digested with purified proteasome complexes. By combining proteasome digestion data with epitope prediction algorithms, candidate epitopes restricted by HLA-A2.1 and other HLA class I molecules were identified. We validated immunogenicity and natural processing of the identified PI epitopes in HLA-A2.1-transgenic mice, while others demonstrated recognition of multiple PI epitopes by CD8+ T cells from T1DM and healthy subjects in the context of different HLA class I molecules. These results demonstrate the power of reverse immunology strategies for epitope discovery. DNA vaccination of HLA-transgenic mice may be another rapid and efficient reverse immunology approach to map additional epitopes derived from other T1DM Ags, such as IA-2 and glutamic acid decarboxylase 65 (GAD 65). Transfer of this information to Elispot- and MHC tetramer-based assay formats should allow to reliably detect and characterize autoreactive CD8+ T cell responses in T1DM, and may open new avenues for early T1DM diagnosis and immune intervention.

Alleles↗
PubMed2005

Complexity, contradictions, and conundrums: studying post-proteasomal proteolysis in HLA class I antigen presentation.

The vast majority of the peptides produced during protein degradation by the cytosolic proteasome-ubiquitin system are consecutively hydrolyzed to single amino acids by multiple cytosolic peptidases preferring intermediate length or short substrates. The small fraction of peptides surviving the aggressive cytosolic environment can be recruited for presentation by major histocompatibility complex (MHC) class I molecules. However, such peptides may frequently have to be adapted to the strict MHC class I-binding requirements by one or several N-terminal-trimming steps. A recent model proposes that an initial step, in which peptides of 15 or more residues are shortened by cytosolic tripeptidylpeptidase II, is followed by additional trimming by cytosolic or endoplasmic reticulum (ER) aminopeptidases. In humans, at least two ER resident aminopeptidases, ERAP1 and ERAP2, contribute to trimming of human leukocyte antigen class I ligands. These interferon-gamma-regulated metallopeptidases show distinct substrate preferences and may have to act in a concerted fashion to remove some complex or longer N-terminal extensions and to trim the full spectrum of precursor peptides. This task is likely facilitated by the formation of presumably heterodimeric ERAP1-2 complexes. RNA interference experiments suggest that both enzymes are important for normal antigen presentation, but precise determination of the extent and the cellular context of their requirement will be left to future experimentation.

Aminopeptidases↗
PubMed2004

Control of cross-presentation during dendritic cell maturation.

The initiation of most cytotoxic immune responses requires MHC class I-restricted presentation of internalized antigens to CD8(+) T lymphocytes, a process called cross-presentation. In dendritic cells (DC), the only antigen-presenting cells that activate naive T cells, cross-presentation is particularly efficient after internalization of opsonized antigens or immune complexes, which are cross-presented through a proteasome- and transporter associated with antigen processing (TAP)-dependent MHC class I antigen presentation pathway. We now show that FcgammaR-mediated cross-presentation is tightly regulated during DC maturation. Cross-presentation increases soon after activation by lipopolysaccharides, and it is then inhibited in fully mature cells. The initial induction of cross-presentation results from an increase of both antigen internalization and delivery to the cytosol, and from a slight rise in the activity of the proteasome and TAP. The subsequent block of cross-presentation in mature DC is a consequence of the selective down-modulation of antigen internalization and cytosolic delivery, while proteasome and TAP activities continue to rise. Therefore, FcgammaR-mediated cross-presentation is regulated during DC maturation by the selective control of antigen internalization and transport to the cytosol.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2002

Beyond the proteasome: trimming, degradation and generation of MHC class I ligands by auxiliary proteases.

The proteasome is now recognized to be implicated in the generation of the vast majority of MHC class I ligands. Moreover, it is probably the only cytosolic protease generating their carboxyterminals. However, solid evidence documents a role of additional and only partly identified proteases in MHC class I antigen processing. Cytosolic tripeptidyl peptidase (TTP II) may be able to carry out some functions normally ascribed to the proteasome, including that of generating antigenic peptides. Several cytosolic enzymes, including bleomycin hydrolase (BH) and puromycin-sensitive aminopeptidase (PSA), but especially the IFNgamma-inducible leucyl aminopeptidase (LAP), can trim the aminoterminal ends of class I ligands. The vast majority of cytosolic peptides is degraded, a process likely to limit antigen presentation, in which thimet oligopeptidase (TOP) may play an important role. Proteolytic activity in the secretory pathway, though much more limited than in the cytosol, also contributes to class I antigen presentation. Signal peptide fragments and peptides at the carboxyterminal end of various proteins targeted to the endoplasmic reticulum can be highly efficient TAP-independent class I ligands. However, an as yet unidentified luminal trimming aminopeptidase may eventually turn out to play the most important role for class I ligand generation in the secretory pathway. Defining the extent of the involvement of cytosolic and luminal peptidases in class I antigen processing will be a challenging task for the future.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMedDate not supplied

[Processing of MHC class I presented antigens].

The immune defences of our organism against pathogens and malignant transformation rely to a large extent on surveillance by cytotoxic T lymphocytes. This surveillance in turn depends on the antigen processing system, which provides peptide samples of the cellular protein composition to MHC (major histocompatibility complex) class I molecules displayed on the cell surface. To continuously and almost in real time provide a representative sample of the array of proteins synthesized by the cell, this system exploits some fundamental pathways of the cellular metabolism, with the help of several dedicated players acting exclusively in antigen processing. Thus, a key element in the turnover of cellular proteins, protein degradation by cytosolic proteasome complexes, is exploited as source of peptides, by recruiting a minor fraction of the produced peptides as ligands for MHC class I molecules. These peptides can be further processed and adapted to the precise binding requirements of allelic MHC class I molecules by enzymes in the cytosol and endoplasmic reticulum. The latter compartment is equipped with several dedicated players helping peptide assembly with class I molecules. These include the TAP (transporter associated with antigen processing) membrane transporter pumping peptides into the ER, and tapasin, a chaperone with a structure similar to MHC molecules that tethers class I molecules awaiting peptide loading to the TAP transporter, and mediates optimization of MHC class I ligand by a still somewhat mysterious mechanism. Additional "house-keeping" chaperones that are known to act in concert in ER quality control, assist and control correct folding, oxidation and assembly of MHC class I molecules. While this processing system handles exclusively endogenous cellular proteins in most cells, dendritic cells employ one or several special pathways to shuttle exogenous, internalized proteins into the system, in a process referred to as cross-presentation. Deciphering the cell biological mechanism creating the link between the endosomal and secretory pathways that enables cross-presentation is one of the challenges faced by contemporary research in the field of MHC class I antigen processing.

Allergy and Immunology↗