Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Origin Recognition Complex”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 1,315 records · Page 73Linked to original sources
PubMed2002

Multiple roles of the RNA polymerase beta subunit flap domain in sigma 54-dependent transcription.

Recent determinations of the structures of the bacterial RNA polymerase (RNAP) and promoter complex thereof establish that RNAP functions as a complex molecular machine that contains distinct structural modules that undergo major conformational changes during transcription. However, the contribution of the RNAP structural modules to transcription remains poorly understood. The bacterial core RNAP (alpha(2)beta beta'omega; E) associates with a sigma (sigma) subunit to form the holoenzyme (E sigma). A mutation removing the beta subunit flap domain renders the Escherichia coli sigma(70) RNAP holoenzyme unable to recognize promoters. sigma(54) is the major variant sigma subunit that utilizes enhancer-dependent promoters. Here, we determined the effects of beta flap removal on sigma(54)-dependent transcription. Our analysis shows that the role of the beta flap in sigma(54)-dependent and sigma(70)-dependent transcription is different. Removal of the beta flap does not prevent the recognition of sigma(54)-dependent promoters, but causes multiple defects in sigma(54)-dependent transcription. Most importantly, the beta flap appears to orchestrate the proper formation of the E sigma(54) regulatory center at the start site proximal promoter element where activator binds and DNA melting originates.

Amino Acid Sequence↗
PubMed1998

Structure of the C-type lectin carbohydrate recognition domain of human tetranectin.

Tetranectin (TN) is a C-type lectin involved in fibrinolysis, being the only endogenous ligand known to bind specifically to the kringle 4 domain of plasminogen. TN was originally isolated from plasma, but shows a wide tissue distribution. Furthermore, TN has been found in the extracellular matrix of certain human carcinomas, whereas none or little is present in the corresponding normal tissue. The crystal structure of full-length trimeric TN (2.8 A resolution) has recently been published [Nielsen et al. (1997). FEBS Lett. 412, 388-396]. The crystal structure of the carbohydrate recognition domain (CRD) of human TN (TN3) has been determined separately at 2.0 A resolution in order to obtain detailed information on the two calcium binding sites. This information is essential for the elucidation of the specificity of TN towards oligosaccharides. TN3 crystallizes as a dimer, whereas it appears as a monomer in solution. The overall fold of TN3 is similar to other known CRDs. Each monomer is built of two distinct regions, one region consisting of six beta-strands and two alpha-helices, and the other region is composed of four loops harboring two calcium ions. The calcium ion at site 1 forms an eightfold coordinated complex and has Asp116, Glu120, Gly147, Glu150, Asn151, and one water molecule as ligands. The calcium ion at site 2, which is believed to be involved in recognition and binding of oligosaccharides, is sevenfold coordinated with ligands Gln143, Asp145, Glu150, Asp165, and two water molecules. One sulfate ion has been located at the surface of TN3, forming contacts to Glu120, Lys148, Asn106 of a symmetry-related molecule, and to an ethanol molecule.

Amino Acid Sequence↗
PubMed1991

Peptide presentation by class-I major histocompatibility complex molecules.

MHC class-I molecules express distinct peptide-binding pockets within their antigen-binding groove. These are critically involved in the binding of antigenic peptides. The amino acid composition of a pocket dictates the structure of a peptide which can be bound in it. This is evident as a consensus amino acid motif which has to exist within a peptide in order for it to bind to a particular MHC allele. Perturbation of a MHC pocket by amino acid substitution can result in the abolition of peptide binding. Less drastic mutations of the peptide-binding groove, particularly the ones away from the critical pocket, can subtly alter the conformation of bound peptide. Both types of substitution exert an influence on the TCR recognition of antigenic peptide. Peptides are also critically involved in the positive selection of the class-I-restricted TCR repertoire in the thymus. These self peptides act by mimicking their foreign antigens. This mimicking involves the binding of self peptides and foreign antigenic peptides to the same pockets of the MHC class-I-antigen binding groove. Consequently, MHC class-I polymorphism in the antigen binding groove controls the intrathymic positive selection and peripheral antigen presentation by the same mechanisms. The majority of positively selecting self peptides could well originate from the extracellular processing of circulating self proteins. Using the diverse, extracellularly generated self peptides and the different determinant density requirements for positive versus negative selection, the immune system can ensure the repertoire diversity, avoiding both the massive clonal deletion of the selected repertoire and the autoreactivity of its T cells.

Amino Acid Sequence↗
PubMed2005

Three-dimensional structures of carbohydrate determinants of Lewis system antigens: implications for effective antibody targeting of cancer.

Lewis system carbohydrate antigens have been shown to be expressed at high levels in many cancers of epithelial cell origin, including those of colon, breast, lung, prostate and ovary. The type 1 (Le(a) and Le(b)) antigens are important histo-blood groups, while type 2 (Le(x) and Le(y)) antigens in healthy individuals are only expressed, at relatively low levels, by a few tissues, including some epithelial cells. Thus, the type 2 antigens are considered to be tumour-associated antigens and are promising targets for cancer treatment, including antibody-based immunotherapy. In this review, we discuss the conformational characteristics of the free and bound forms of Lewis oligosaccharides and the 3D structures of antibodies in complex with Le(y) and Le(x) antigens. Collectively, the structural studies have demonstrated that the Lewis determinants are rigid structures, which generally maintain the same conformation in the free and bound states. The rigid nature and similarities in shape of type 1 and 2 Lewis oligosaccharides appear to make them perfectly suited to driving a structurally convergent immune response (at least in the case of Le(y) specific antibodies) toward a highly specific recognition of individual carbohydrate determinants, which is a goal in the development of effective antibody-based cancer treatments.

Animals↗
PubMed1990

The soluble viral glycoprotein of vesicular stomatitis virus efficiently sensitizes target cells for lysis by CD4+ T lymphocytes.

The soluble glycoprotein Gs of vesicular stomatitis virus (VSV), at approximately 10(4) molecules per cell, sensitized target cells for lysis by clones of CD4+ cytolytic T lymphocytes (CTL). In addition to lysis, the clones responded by proliferation and interleukin-2 release. Targets sensitized by Gs competed effectively with VSV-infected cells for recognition. Immune cytolysis by these CD4+ CTLs was restricted by class II major histocompatibility complex (MHC) antigens and was specific to VSV. The specific class II MHC antigen which was restricting for each clone remained the same whether the targets were sensitized by infection with VSV or by exogenously added soluble antigen. Sensitization by Gs appeared to require prior processing because the antigen-presenting cells that were fixed prior to exposure to Gs failed to be recognized by the CTL clones. The high efficiency of this uptake and processing was suggested by the inability of Gs at concentrations up to 10(7) per cell to block superinfection by VSV or to effect the RNA-synthetic machinery of uninfected cells. Also, Gs failed to hemolyze sheep erythrocytes when there was hemolysis by virions or an amino-terminal peptide of the VSV glycoprotein. Extrapolation of these results to viral diseases was possible because soluble viral glycoproteins were naturally synthesized during many viral infections and class II MHC antigens were inducible in cells of nonlymphoid origin. Therefore, CD4+ CTLs may be important participants in increasing virus-induced pathology, especially among adjacent uninfected cells.

Animals↗
PubMed1999

Origins of Enantioselectivity with Nitrogen-Sulfur Chelate Ligands in Palladium-Catalyzed Allylic Substitution.

The reaction of 1,3-diphenyl-2-propenyl acetate (9) with dimethylmalonate to give the substitution product 10 is effectively catalyzed by Pd complexes containing chiral imine-sulfide chelate ligands derived from amino acids. The ligand of choice, (S)-N-2'-chlorobenzylidene-2-amino-3-methyl-1-thiophenylbutane (6e), prepared in only two steps from (S)-valinol, gave an ee of 94%. Because the explanation of selectivity with the majority of other nitrogen-sulfur chelate ligands in this reaction assumes the selectivity to be controlled by an electronic bias, which contradicts our results, we characterized the Pd-allyl intermediate 14 by X-ray diffraction and solution NMR. The possible mechanism of chirality transfer is discussed. The site of nucleophilic attack on the allyl ligand is not trans to the perceived better pi-acceptor ligand (sulfur), which would be analogous to chiral nitrogen-phosphorus systems. This reaction occurs trans to the imine donor, and the enantioselectivity is ultimately controlled by the subtle steric environment of the chiral imine-sulfur chelate ligand, which predisposes the allyl unit of the reaction intermediate to a preferred reaction trajectory. In light of results that emphasize the power of electronic desymmetrization for chiral recognition, these results suggest that electronically dissimilar ligands may not give rise to chiral recognition through electronic dissimilarity.

Journal Article↗
PubMed1980

Surface receptors on lymphoreticular cells: sensory devices for host recognition of foreign antigens and neoplasia.

Distinct types of cells in the lymphoreticular system regulate an individual's immunologic homeostasis and response to disease. By means of multiple receptors the cell membrane transfers signals between the environment and the cell. This article reviews the important surface antigens and receptors on normal and activated macrophages (e.g., receptors for the crystallizable fragment [Fc] of immunoglobulin), on lymphocytes derived from the bone marrow (e.g., immunoglobulins and immune-associated [Ia] antigens), on thymus-derived lymphocytes (e.g., Thy-1 antigens) and on "null' cells. Although many of these markers were originally defined in rodents and birds, analogous markers in humans have proved extremely useful in characterizing lymphoreticular cell populations in healthy and sick individuals. Established and postulated functions of the markers in host defence mechanisms are discussed.

Antigens, Neoplasm↗
PubMed1988

Structure and organization of Marchantia polymorpha chloroplast genome. I. Cloning and gene identification.

We have determined the complete nucleotide sequence of chloroplast DNA from a liverwort, Marchantia polymorpha, using a clone bank of chloroplast DNA fragments. The circular genome consists of 121,024 base-pairs and includes two large inverted repeats (IRA and IRB, each 10,058 base-pairs), a large single-copy region (LSC, 81,095 base-pairs), and a small single-copy region (SSC, 19,813 base-pairs). The nucleotide sequence was analysed with a computer to deduce the entire gene organization, assuming the universal genetic code and the presence of introns in the coding sequences. We detected 136 possible genes. 103 gene products of which are related to known stable RNA or protein molecules. Stable RNA genes for four species of ribosomal RNA and 32 species of tRNA were located, although one of the tRNA genes may be defective. Twenty genes encoding polypeptides involved in photosynthesis and electron transport were identified by comparison with known chloroplast genes. Twenty-five open reading frames (ORFs) show structural similarities to Escherichia coli RNA polymerase subunits, 19 ribosomal proteins and two related proteins. Seven ORFs are comparable with human mitochondrial NADH dehydrogenase genes. A computer-aided homology search predicted possible chloroplast homologues of bacterial proteins; two ORFs for bacterial 4Fe-4S-type ferredoxin, two for distinct subunits of a protein-dependent transport system, one ORF for a component of nitrogenase, and one for an antenna protein of a light-harvesting complex. The other 33 ORFs, consisting of 29 to 2136 codons, remain to be identified, but some of them seem to be conserved in evolution. Detailed information on gene identification is presented in the accompanying papers. We postulated that there were 22 introns in 20 genes (8 tRNA genes and 12 ORFs), which may be classified into the groups I and II found in fungal mitochondrial genes. The structural gene for ribosomal protein S12 is trans-split on the opposite DNA strand. The universal genetic code was confirmed by the substitution pattern of simultaneous codons, and by possible codon recognition of the chloroplast-encoded tRNA molecules, assuming no importation of tRNA molecules from the cytoplasm. The nucleotide residue A or T is preferred at the third position of the codons (G+C, 11.9%) and in intergenic spacers (G+C, 19.5%), resulting in an overall G+C content that is low (28.8%) throughout the liverwort chloroplast genome. Possible gene expression signals such as promoters and terminators for transcription, predicted locations of gene products, and DNA replicative origins are discussed.

Base Sequence↗
PubMed1982

Immune recognition of serum albumin--XIV. Cross-reactivity by T-lymphocyte proliferation of subdomains 3, 6 and 9 of bovine serum albumin.

Recently, we have shown that, with rabbit antibodies against BSA, the BSA fragments 115-184, 307-285 and 505-582 (essentially corresponding to subdomains 3, 6 and 9 of BSA) exhibit a cross-reaction which increases remarkably with the time antisera are obtained after the initial immunization. In the present report, we have examined whether this cross-reaction at the B-cell level takes place also at the T-cell level. Optimum conditions for T-cell proliferation to BSA and the three fragments were determined in terms of priming dose, challenging dose, time lymph nodes are obtained after immunization and finally duration of culture. Several strains of mice representing independent haplotypes and recombinant strains were examined for their responsiveness to BSA by T-lymphocyte proliferation, performed in the respective preimmune sera of the same mice. This afforded the identification of high- and low-responder strains to BSA. It was determined that the immune response to BSA is controlled by genes in the I-A subregion of the H-2 gene complex with some slight non-H-2 influences. In order to avoid the possibility of genetic exclusion of response to a given antigenic site and to improve the change of total site recognition, two high-responder strains (B10.M and B10.G) were crossed. Antibodies raised in (B10.M X B10.G)F1 mice recognized subdomains 3, 6 and 9 and these were found to be cross-reactive. Specific 125I-labelled antibodies isolated on a given subdomain-adsorbent were bound very well by adsorbents of the other two subdomains. T-cells from the F1 mice that had been primed with subdomain 3 responded to subdomain 3 and were also high responders to subdomain 6 and intermediate responders to subdomain 9. After priming with subdomain 6, the T-cells responded equally as well to subdomains 3 or 6 and slightly to subdomain 9. Finally, priming with subdomain 9, gave T-cells that responded to subdomain 9 and also gave high responses to subdomains 3 or 6. It was concluded that the cross-reactions originally observed at the B-cell level also take place at the T-cell level.

Animals↗
PubMed1998

Characterization of human hect domain family members and their interaction with UbcH5 and UbcH7.

The hect domain protein family was originally identified by sequence similarity of its members to the C-terminal region of E6-AP, an E3 ubiquitin-protein ligase. Since the C terminus of E6-AP mediates thioester complex formation with ubiquitin, a necessary intermediate step in E6-AP-dependent ubiquitination, it was proposed that members of the hect domain family in general have E3 activity. The hect domain is approximately 350 amino acids in length, and we show here that the hect domain of E6-AP is necessary and sufficient for ubiquitin thioester adduct formation. Furthermore, the human genome encodes at least 20 different hect domain proteins, and in further support of the hypothesis that hect domain proteins represent a family of E3s, several of these are shown to form thioester complexes with ubiquitin. In addition, some hect domain proteins interact preferentially with UbcH5, whereas others interact with UbcH7, indicating that human hect domain proteins can be grouped into at least two classes based on their E2 specificity. Since E3s are thought to play a major role in substrate recognition, the presence of a large family of E3s should contribute to ensure the specificity and selectivity of ubiquitin-dependent proteolytic pathways.

Amino Acid Sequence↗
PubMed1999

APCs express DCIR, a novel C-type lectin surface receptor containing an immunoreceptor tyrosine-based inhibitory motif.

We have identified a novel member of the calcium-dependent (C-type) lectin family. This molecule, designated DCIR (for dendritic cell (DC) immunoreceptor), is a type II membrane glycoprotein of 237 aa with a single carbohydrate recognition domain (CRD), closest in homology to those of the macrophage lectin and hepatic asialoglycoprotein receptors. The intracellular domain of DCIR contains a consensus immunoreceptor tyrosine-based inhibitory motif. A mouse cDNA, encoding a homologous protein has been identified. Northern blot analysis showed DCIR mRNA to be predominantly transcribed in hematopoietic tissues. The gene encoding human DCIR was localized to chromosome 12p13, in a region close to the NK gene complex. Unlike members of this complex, DCIR displays a typical lectin CRD rather than an NK cell type extracellular domain, and was expressed on DC, monocytes, macrophages, B lymphocytes, and granulocytes, but not detected on NK and T cells. DCIR was strongly expressed by DC derived from blood monocytes cultured with GM-CSF and IL-4. DCIR was mostly expressed by monocyte-related rather than Langerhans cell related DC obtained from CD34+ progenitor cells. Finally, DCIR expression was down-regulated by signals inducing DC maturation such as CD40 ligand, LPS, or TNF-alpha. Thus, DCIR is differentially expressed on DC depending on their origin and stage of maturation/activation. DCIR represents a novel surface molecule expressed by Ag presenting cells, and of potential importance in regulation of DC function.

Amino Acid Sequence↗
PubMed1992

Auditory/verbal and visual/spatial memory in children with complex partial epilepsy of temporal lobe origin.

Two groups of epileptic children and a normal control group were administered a Comprehensive Children's Memory Scale (Experimental Edition) which is presently being developed by this author. The first experimental group consisted of 12 children having complex partial seizures of left temporal origin and the second group consisted of 12 children having partial complex seizures of right temporal lobe origin based upon clinical description and EEG/neuroimaging verification. Results indicated: (a) Children with left temporal lobe epilepsy demonstrated significantly lower performance than controls on auditory/verbal memory testing. (b) Children with right temporal lobe epilepsy demonstrated significantly lower performance than controls on visual/spatial memory testing. (c) For the most part, the right and left temporal lobe groups did not significantly differ from each other. However, their performance was in the expected direction; i.e., children with left temporal lobe epilepsy scored lower than right temporal lobe epileptics on auditory/verbal memory testing, and children with right temporal lobe epilepsy scored lower than left temporal lobe epileptics on visual/spatial memory testing.

Attention↗
PubMed1999

Two new members of the emerging KDWK family of combinatorial transcription modulators bind as a heterodimer to flexibly spaced PuCGPy half-sites.

Initially recognized as a HeLa factor essential for parvovirus DNA replication, parvovirus initiation factor (PIF) is a site-specific DNA-binding complex consisting of p96 and p79 subunits. We have cloned and sequenced the human cDNAs encoding each subunit and characterized their products expressed from recombinant baculoviruses. The p96 and p79 polypeptides have 40% amino acid identity, focused particularly within a 94-residue region containing the sequence KDWK. This motif, first described for the Drosophila homeobox activator DEAF-1, identifies an emerging group of metazoan transcriptional modulators. During viral replication, PIF critically regulates the viral nickase, but in the host cell it probably modulates transcription, since each subunit is active in promoter activation assays and the complex binds to previously described regulatory elements in the tyrosine aminotransferase and transferrin receptor promoters. Within its recognition site, PIF binds coordinately to two copies of the tetranucleotide PuCGPy, which, remarkably, can be spaced from 1 to 15 nucleotides apart, a novel flexibility that we suggest may be characteristic of the KDWK family. Such tetranucleotides are common in promoter regions, particularly in activating transcription factor/cyclic AMP response element-binding protein (ATF/CREB) and E-box motifs, suggesting that PIF may modulate the transcription of many genes.

Amino Acid Motifs↗
PubMed2000

The mouse tumor cell lines EL4 and RMA display mosaic expression of NK-related and certain other surface molecules and appear to have a common origin.

As a potential means for facilitating studies of NK cell-related molecules, we examined the expression of these molecules on a range of mouse tumor cell lines. Of the lines we initially examined, only EL4 and RMA expressed such molecules, both lines expressing several members of the Ly49 and NKRP1 families. Unexpectedly, several of the NK-related molecules, together with certain other molecules including CD2, CD3, CD4, CD32, and CD44, were often expressed in a mosaic manner, even on freshly derived clones, indicating frequent switching in expression. In each case examined, switching was controlled at the mRNA level, with expression of CD3zeta determining expression of the entire CD3-TCR complex. Each of the variable molecules was expressed independently, with the exception that CD3 was restricted to cells that also expressed CD2. Treatment with drugs that affect DNA methylation and histone acetylation could augment the expression of at least some of the variable molecules. The striking phenotypic similarity between EL4 and RMA led us to examine the state of their TCRbeta genes. Both lines had identical rearrangements on both chromosomes, indicating that RMA is in fact a subline of EL4. Overall, these findings suggest that EL4 is an NK-T cell tumor that may have retained a genetic mechanism that permits the variable expression of a restricted group of molecules involved in recognition and signaling.

Acetylation↗
PubMed1994

Regulation of human dioxin receptor function by indolocarbazoles, receptor ligands of dietary origin.

The intracellular basic helix-loop-helix (bHLH) dioxin receptor mediates signal transduction by dioxin (2,3,7,8-tetrachlorodibenzo-p-dioxin). In analogy to nuclear receptors that are members of the steroid hormone receptor superfamily the dioxin receptor is a ligand-inducible transcriptional regulator that directly binds to response elements within regulated genes. The most commonly studied dioxin receptor ligands are dioxin itself and structurally related environmental contaminants. A physiological ligand has not yet been identified. Interestingly, however, indolo[3,2-b]carbazole, a compound formed from precursors in the diet, has been shown to bind the murine dioxin receptor with high affinity in vitro. In the present study we show that this compound and its methylated derivative 5,11-dimethylindolo[3,2-b]carbazole very potently activated transcription from a dioxin or xenobiotic response element (XRE)-driven reporter gene in both murine and human hepatoma cells. This effect was not observed in mutant, dioxin-resistant hepatoma cells which are either deficient in expression of dioxin receptor or the bHLH receptor partner factor Arnt. In vitro indolocarbazoles induced XRE binding activity by the human dioxin receptor-Arnt complex in a dose-dependent manner. Thus, both dioxin- and indolocarbazole-activated forms of dioxin receptor regulate target gene expression by the same mechanism involving recruitment of the bHLH factor Arnt and recognition of the XRE element. Finally, the indolo[3,2-b]carbazole-activated human dioxin receptor appeared to generate more stable complexes with the XRE target sequence relative to those produced by the dioxin-activated receptor form, indicating interesting mechanistic differences between different classes of dioxin receptor ligands in their abilities to modulate human dioxin receptor function.

Animals↗
PubMed1996

A structural basis for the preferential binding of hemimethylated DNA by HhaI DNA methyltransferase.

The crystal structure of HhaI methyltransferase complexed with non-palindromic duplex DNA, containing a hemimethylated recognition sequence, and with the cofactor analog S-adenosyl-L-homocysteine (AdoHcy), has been determined. The structure provides an explanation for the stronger affinities of DNA methyltransferases for hemimethylated DNA than for unmethylated or fully methylated DNA in the presence of AdoHcy. The unmethylated target 2'-deoxycytidine flips out of the DNA helix and the CH group at position 5 makes van der Waals' contacts with the sulfur atom of AdoHcy. Selectivity/preference for hemimethylated over fully methylated DNA may thus reflect interactions among the chemical substituent (H or CH3) at the C5 position of the flipped cytosine, protein and the bound AdoHcy. The 5-methyl-2'-deoxycytidine on the complementary strand remains in the DNA helix, with the methyl group almost perpendicular to the carboxylate group of Glu239, which is part of the sequence recognition loop. Thus, selectivity/preference for hemimethylated over unmethylated DNA appears to result largely from van der Waals' contacts between the planar Glu239 carboxylate and the methyl group of the 5-methyl-2'-deoxycytidine. Furthermore, the positive electrostatic potential originating from the bound AdoHcy extends to the DNA phosphate groups flanking the flipped cytosine. The increased binding to DNA by long-range electrostatic interactions should also occur with the methyl donor S-adenosyl-L-methionine.

Amino Acid Sequence↗
PubMed2005

Immunostimulatory functions of membrane-bound and exported heat shock protein 70.

In the search for tumor-specific antigens, microbial and eukaryotic heat shock proteins (HSP) have been identified. Intracellularly, HSPs function as molecular chaperones supporting folding and transport of a great variety of polypeptides and proteins under normal physiological conditions and following stress stimuli. Furthermore, interferon-gamma and elevated body temperature induced by exercise have been found to increase serum levels of HSPs in humans. Extracellularly localized or plasma membrane-bound HSPs elicit a potent anti-cancer immune response mediated either by the adaptive or innate immune system. Following uptake of HSP (HSP70 and gp96)-peptide complexes by antigen presenting cells (APCs) and "cross-presentation" of HSP-chaperoned peptides on MHC class I molecules, a CD8-specific T cell response is induced. Apart from chaperoning tumor-specific peptides, HSPs per se provide activatory signals for the innate immune system. Binding of peptide-free HSP70 to APCs via Toll-like receptors (TLRs) initiates the secretion of pro-inflammatory cytokines and thus results in a broad non-specific immunostimulation. An unusual membrane localization of Hsp70, the major heat-inducible member of the HSP70 family, on tumor cells but not on corresponding normal tissues was found to act as a tumor-specific recognition structure for natural killer (NK) cells. Soluble as well as cell membrane-bound HSP70 can directly activate the cytolytic and migratory capacity of NK cells. APCs and tumor cells actively release HSP70s in lipid vesicles with biophysical properties of exosomes. These HSP70-presenting exosomes are thought to stimulate the adaptive and innate immune system in vivo. Taken together, depending on their intra/extracellular localization, peptide loading status, origin and route of application, HSPs either exert immune activation as danger signals in cancer immunity or protect cells from lethal damage induced by exogenous stress stimuli.

CD8-Positive T-Lymphocytes↗
PubMed1997

A naturally processed peptide presented by HLA-A*0201 is expressed at low abundance and recognized by an alloreactive CD8+ cytotoxic T cell with apparent high affinity.

In contrast to T cells that respond to peptides presented by self MHC molecules, alloreactive T cells recognize determinants expressed on nonself MHC molecules. Because current positive selection models suggest that T cell affinity toward a nonself MHC molecule would be lower than that toward a self MHC molecule, we previously proposed that vigorous alloreactive responses would be generated preferentially toward those antigenic peptide complexes presented at the highest density on the cell surface. The high abundance of two class I MHC-associated peptides that have been identified as allo- or xenoantigens is consistent with this hypothesis. We report here the identification of a naturally processed peptide YLDPAQQNL that is presented by HLA-A*0201 and recognized by an alloreactive T cell clone. This peptide appears to originate from an unknown member of the zinc finger proteins. Quantitation by mass spectrometry indicates that this peptide is present on the surface at 85 to 125 copies per cell, comparable with the density of several other epitopes presented by HLA-A*0201 to self MHC-restricted T cells. In addition, based on the affinity of the peptide for HLA-A*0201 and the half-maximal peptide concentration required for T cell sensitization, this alloreactive T cell appears to have an affinity similar to or higher than that of many self MHC-restricted T cells. These data suggest that allogeneic responses can be directed against antigenic determinants of low abundance and that recognition of alloreactive peptides is not limited by a lower affinity of T cells for nonself MHC molecules.

Clone Cells↗