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P Walden

Publications and source records attributed to P Walden.

11 recordsLinked to original sources
PubMed1992

Proteasome subunits encoded by the major histocompatibility complex are not essential for antigen presentation.

Major histocompatibility complex (MHC) class I molecules bind and deliver peptides derived from endogenously synthesized proteins to the cell surface for survey by cytotoxic T lymphocytes. It is believed that endogenous antigens are generally degraded in the cytosol, the resulting peptides being translocated into the endoplasmic reticulum where they bind to MHC class I molecules. Transporters containing an ATP-binding cassette encoded by the MHC class II region seem to be responsible for this transport. Genes coding for two subunits of the '20S' proteasome (a multicatalytic proteinase) have been found in the vicinity of the two transporter genes in the MHC class II region, indicating that the proteasome could be the unknown proteolytic entity in the cytosol involved in the generation of MHC class I-binding peptides. By introducing rat genes encoding the MHC-linked transporters into a human cell line lacking both transporter and proteasome subunit genes, we show here that the MHC-encoded proteasome subunit are not essential for stable MHC class I surface expression, or for processing and presentation of antigenic peptides from influenza virus and an intracellular protein.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1991

Exact prediction of a natural T cell epitope.

T lymphocytes recognize their antigen as peptides associated with major histocompatibility complex (MHC) molecules. Peptides naturally presented by MHC class I molecules are uniform in length and have a specific motif, both defined by the respective MHC allele (Falk, K. et al. Nature 1991. 351:290). These allele-specific motifs should allow exact prediction of natural T cell epitopes. H-2Kb-restricted epitopes, for example, have a length of eight amino acid residues and conserved anchor residues at positions 5 and 8. According to this information, we predicted the natural Kb-restricted epitope of ovalbumin, thought to be contained in the 19-mer IINFEKLTEWTSSNVMEER, to be SIINFEKL. Here we show that this prediction is correct. Thus, exact prediction of natural T cell epitopes is possible.

Amino Acid Sequence↗
PubMed1988

T cell response to myoglobin: a comparison of T cell clones in high-responder and low-responder mice.

Mice carrying the H-2b haplotype (e.g., inbred strains C57BL/6 and C57BL/10) are low responders to sperm whale myoglobin when tested in the T cell proliferation assay. Their response is improved by the removal of the Ly-2+ cells from the lymph node population, but it still remains significantly lower than that of cells cells from high-responder strains (e.g., DBA/2, H-2d). To determine whether T cells from the low and high-responder mice recognize the same or different epitopes on the immunizing antigen, we obtained sets of T cell clones from both strains and tested them against peptides representing different regions of the myoglobin molecule, as well as against myoglobins from species other than the sperm whale. Four types of T cell clones were obtained from the DBA/2 mice: 3 types responded to the peptide 107-120 (9 clones altogether), and 1 type responded to the peptide 133-149 (4 clones altogether). The 3 types responding to the peptide 107-120 could be distinguished by their response to horse myoglobin or by the restriction of the response (Ad vs. Ed). Similarly, 5 types of T cell clones were obtained from the C57BL/6 mice: 2 types responded to the peptide 10-22 (1 type, but not the other, responded to horse myoglobin); 1 type responded to the peptide 133-149; and 2 types did not respond to any of the peptides used (1 type, but not the other, responded to dog myoglobin). All 5 types (13 clones altogether) were presumably Ab restricted. These results demonstrate the diversity of epitopes in single antigenic regions and show equivalent heterogeneity of T cell repertoires in high and low responder mice. Attempts to demonstrate specific T cell suppression in the low responder mice failed; only partial, nonspecific suppression was observed.

Animals↗
PubMed1988

Antigen presentation by liposomes as model system for T-B cell interaction.

Using the earlier established liposome system for antigen presentation, in which liposomes bearing major histocompatibility complex (MHC)-class II molecules inserted into and protein antigen covalently linked to the membrane were found to be sufficient for an antigen-specific and MHC-restricted activation of T cells, the minimal requirements for T-B cell interaction were investigated. Liposomes carrying MHC class II molecules and antigen-specific monoclonal antibodies were constructed and tested for their ability to present soluble antigen to T cells. With the antigens lactate dehydrogenase B and pigeon cytochrome c, a specific stimulation of T cell clones and hybridomas could be obtained. These results demonstrate the possibility of a direct involvement of the immunoglobulins on the B cell surface in their interaction with T cells.

Animals↗
PubMed1986

Antigen presentation by liposomes: inhibition with antibodies.

The involvement of both antigen and class II major histocompatibility complex (MHC) molecules in T cell activation by liposome-bound antigens was investigated. We used a pigeon cytochrome c (PCC)-specific Ek-restricted T cell hybridoma that can be activated to produce interleukin 2 by liposomes carrying either PCC and Ek molecules, or a high concentration of PCC alone. We demonstrated that the MHC-restricted response of this hybridoma to liposomes is specifically blocked by both anti-MHC and anti-PCC monoclonal antibodies, whereas unrestricted activation is only inhibited by PCC-specific antibody.

Animals↗
PubMed1986

Major histocompatibility complex-restricted and unrestricted activation of helper T cell lines by liposome-bound antigens.

Helper T lymphocytes recognize foreign antigen together with class II major histocompatibility complex (Mhc) molecules on the surface of antigen-presenting cells (APC). However, it is not known in what form soluble protein antigens are presented to T cells. The difficulty of serologically demonstrating the presence of soluble antigen on the surface of APC, the observed rapid degradation of antigen by these cells, and the finding that under special circumstances peptides of a certain protein are more antigenic that the whole molecule have led to the notion that foreign antigens must be rendered immunogenic for helper T cells by internalization, processing (probably involving enzymatic fragmentation), and redisplay on the membrane of APC in association with class II Mhc molecules. To analyze antigen recognition by helper T cells and to assess the biological significance of antigen processing, we have constructed liposomes that carry inserted class II Mhc molecules and a protein antigen coupled covalently to one of the lipid constituents of the artificial membrane. We demonstrate here that such liposomes are capable of inducing proliferative responses of long-term cultured T-cell clones, and interleukin-2 (Il-2) production by a T-cell hybridoma in an antigen-specific, Mhc-restricted fashion, in the absence of antigen-presenting cells. The responses require the presence of foreign antigen and class II molecules on the same lipid vesicles. The magnitude of responses is critically dependent on the lipid composition, the density of bound antigen, and the concentration of liposomes in cell cultures.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1985

Fine specificity analysis of lactate dehydrogenase B-specific proliferating T cell clones: implications for the mechanism of alloreactivity.

T cell clones of C57BL/6 origin which recognize porcine lactate dehydrogenase B (LDH-BP) together with the Ab molecule were characterized in terms of fine specificity for both LDH-B and self-major histocompatibility complex determinants. Using antigen-presenting cells from the Ab-mutant strain B6.C-H-2bm12 (bm12), three clonotypes could be distinguished: the first responds to LDH-BP + bm12, the second fails to respond and the third is alloreactive to bm12. The last clone exhibits additional alloreactivities to A molecules expressed in strains of H-2 haplotypes f, r, s, u, w6, w7, w16, w17 and w23. All three clonotypes give identical response patterns to a panel of 17 different dehydrogenase enzymes, and react to the same tryptic peptide of LDH-BP. Thus, these clones appear to recognize the same LDH-B epitope together with at least 3 different determinants of the Ab molecule. The data suggest that alloreactivity is more closely related to T cell specificity for self-major histocompatibility complex than to specificity for foreign antigen.

Animals↗
PubMedDate not supplied

Induction of regulatory T-lymphocyte responses by liposomes carrying major histocompatibility complex molecules and foreign antigen.

Regulatory (helper and suppressor) T lymphocytes become activated only when foreign antigen is presented to them on the surface of antigen-presenting cells (APC), together with class II major histocompatibility complex (MHC) molecules (heterodimers of polypeptides of 28,000 and 35,000 relative molecular mass). Once activated by a certain foreign antigen--MHC combination, T cells react to the same antigen only in combination with the same MHC molecule, a phenomenon termed MHC restriction of T-cell recognition (reviewed in refs 1,5). Studies of the mechanisms involved in antigen presentation and MHC restriction have been hampered mainly by the virtual impossibility of inducing T-cell responses in the absence of APC. We describe here the production of synthetic lipid vesicles with inserted class II MHC molecules and a protein antigen coupled covalently to the lipid. These liposomes are shown to stimulate cloned helper T cells and T-cell hybridomas in an antigen-specific, MHC-restricted manner in the absence of APC. Thus, the recognition of foreign antigen together with class II MHC molecules seems to be the only signal required for the activation of antigen-primed regulatory T cells. Furthermore, 'processing' of antigen by APC is not essential for its recognition by T cells.

Animals↗