HIV-epitope-specific T cell responses are critical components of the natural immune response to HIV infection, but these cells often become dysfunctional in chronic infection. Structural diversity within the epitope-specific T cell receptor (TCR) repertoire is likely beneficial in the suppression of viral epitope variants. However, the relationship between the structural and clonotypic composition of the HIV-specific TCR repertoire, clonotypic surface and functional phenotype, and avidity for and exposure to antigen is poorly defined. Dominant and sub-dominant epitope-specific T cell clonotypes were identified and the TCR repertoire was assessed over time. Surface expression of PD-1, CD38, CD127, CD45RO, and CCR7 was measured and used to define exhaustion and memory profiles on epitope-specific T cell populations during chronic infection and after initiation of antiretroviral therapy. Dominant clonotypes in chronic infection express a surface phenotype consistent with exhaustion which is ...
BACKGROUNDː The most cause of cancer-related death in women population is breast cancer (BC). Hence, efforts to develop an effective treatment against BC are needed. Since the large proportion of BC is due to over-expression of tumor-associated antigens (TAAs), multi-epitope cancer vaccines are considered as a promising therapeutic approach. The aim of the current study is the production of the novel multi-epitope peptide vaccine against BC in a prokaryotic host. Our novel multi-epitope BC vaccine consists of four sections: 1) cytotoxic T lymphocytes epitopes from human epidermal growth factor receptor, heparanase, mucin 1 protein; 2) helper T lymphocytes epitopes from survivin; 3) a segment of Por B protein a immunostimulatory adjuvant, which was selected from Neisseria meningitides by bioinformatics analysis; 4) a segment of murine ULBP-like transcript 1, which binds to a natural killer group 2 member D receptor in tumor microenvironment with high affinity and stimulates innate immune ...
CD8+ T cells have the potential to control HSV-2 infection. However, limited information has been available on CD8+ T cell epitopes or the functionality of antigen specific T cells during infection or following immunization with experimental vaccines. Peptide panels from HSV-2 proteins ICP27, VP22 and VP13/14 were selected from in silico predictions of binding to human HLA-A*0201 and mouse H-2Kd, Ld and Dd molecules. Nine previously uncharacterized CD8+ T cell epitopes were identified from HSV-2 infected BALB/c mice. HSV-2 specific peptide sequences stabilized HLA-A*02 surface expression with intermediate or high affinity binding. Peptide specific CD8+ human T cell lines from peripheral blood lymphocytes were generated from a HLA-A*02+ donor. High frequencies of peptide specific CD8+ T cell responses were elicited in mice by DNA vaccination with ICP27, VP22 and VP13/14, as demonstrated by CD107a mobilization. Vaccine driven T cell responses displayed a more focused immune response than those induced
Free resource for searching and exporting immune epitopes. Includes more than 95% of all published infectious disease, allergy, autoimmune, and transplant epitope data.
Advances in the field of T cell immunology have contributed to the understanding that cross-reactivity is an intrinsic characteristic of the T cell receptor (TCR), and that each TCR can potentially interact with many different T cell epitopes. To better define the potential for TCR cross-reactivity between epitopes derived from the human genome, the human microbiome, and human pathogens, we developed a new immunoinformatics tool, JanusMatrix, that represents an extension of the validated T cell epitope mapping tool, EpiMatrix. Initial explorations, summarized in this synopsis, have uncovered what appear to be important differences in the TCR cross-reactivity of selected regulatory and effector T cell epitopes with other epitopes in the human genome, human microbiome, and selected human pathogens. In addition to exploring the T cell epitope relationships between human self, commensal and pathogen, JanusMatrix may also be useful to explore some aspects of heterologous immunity and to examine T cell
Jørgensen KW, Rasmussen M, Buus S, Nielsen M. NetMHCstab - predicting stability of peptide:MHC-I complexes; impacts for CTL epitope...
The specificity of T cells is determined by the TCR. T cell populations activated and expanded during most in vivo antigen challenges are highly complex, with diverse TCR repertoires, complicating the detection of these cells. The ideal reagent to identify complex epitope-specific T cell populations would be the natural ligand of the TCR, the MHC/epitope complex. However, the affinity of the TCR-MHC/epitope interaction is very low; the association is characterized by a particularly high dissociation rate. To increase the overall avidity of this interaction, MHC/epitope complexes are multimerized into e.g. tetramers. MHC tetramer reagents conjugated with a fluorescent dye can be used in flow cytometry, allowing highly specific detection and isolation of (complex) epitope specific T cell populations directly ex vivo.. The generation of MHC class I multimer reagents has become well established over the past few years. Beta-2-microglobulin and the heavy chains (HC) of MHC molecules are expressed as ...
TCR affinity associated with functional differences between dominant and subdominant SIV epitope-specific CD8+ T cells in Mamu-A*01+ rhesus monkeys.
Free resource for searching and exporting immune epitopes. Includes more than 95% of all published infectious disease, allergy, autoimmune, and transplant epitope data.
Strategy for Identifying Dendritic Cell-Processed CD4 T Cell Epitopes from the HIV Gag p24 Protein. . Biblioteca virtual para leer y descargar libros, documentos, trabajos y tesis universitarias en PDF. Material universiario, documentación y tareas realizadas por universitarios en nuestra biblioteca. Para descargar gratis y para leer online.
ECIA™ Intracellular cytokine staining assay is utilized to detect the antigen-specific T cell responses, immunogenic analysis, epitope discovery at a single cell level for both clinical studies and scientific researches.
We have recently described the first true genome-wide screen for CD4+ T cell reactivity directed against MTB in latent TB infected individuals. The approach relied on predictions of HLA binding capacity for a panel of DR, DP and DQ alleles representative of those most commonly expressed in the general population, coupled with high throughput ELISPOT assays. The results identified hundreds of novel epitopes and antigens, and documented the novel observation that T cells in latent MTB infection are confined to the CXCR3+CCR6+ phenotype and largely directed against three antigenic
... provides a collection of methods from computational immunology for the development of novel epitope-based vaccines including HLA ligand or potential T-Cell epitope prediction, an epitope selection framework for vaccine design, and a method to design optimal string-of-beads vaccines. Additionally, EpiToolKit provides several other tools ranging from HLA typing based on NGS data, to prediction of polymorphic peptides ...
The present study focused on three Gag CTL epitopes restricted by three common HLA alleles in Japanese people (24). The Gag protein is most commonly targeted by CTL-inducing HIV/AIDS vaccines (15). In our endogenous expression system, three A*0201-restricted epitope variants and one B*5101-restricted epitope variant escaped from the wild-type CTL recognition, and four A24-restricted epitope variants escaped from the A24-restricted 3R mutant-reactive CTL recognition. Intriguingly, two A*0201-restricted variants and three A24-restricted variants escaped from CTL killing when the gag clones were expressed endogenously in the target cells by the HIV-1 vector, despite the fact that the synthetic variant peptides were well recognized by the CTLs when loaded onto the MHC class I molecule exogenously. The peptide titration experiments have revealed that the strength of these variant peptides recognition was almost equivalent to that of the A*0201-restricted wild-type peptide or the A24-restricted 3R ...
The interaction between a CD4+ TH cell and an antigen presenting cell (APC) is a finely tuned event in adaptive immunity. The affinity is dictated by the T cell receptor (TCR) and the characteristics of antigenic peptide epitopes presented on the major histocompatibility complex class II (pMHC class II) molecules on APCs. Due to the high degree of polymorphism in MHC molecules and the vast repertoire of epitopes that may be presented on each, it is an immense challenge to predict epitopes relevant to disease and homeostasis. It would therefore be of very high value to develop a technology that allows for precise experimental identification of T cell epitopes in the absence of any prior knowledge of the relevant antigen, as long as one has access to T cells. We have developed a novel and generic combinatorial display system for MHC class II, based on phage display. Using phage display, one can probe an epitope sequence space orders of magnitude larger than any cellular or chemical system. As a ...
TY - JOUR. T1 - Refinement in the production and purification of recombinant HCMV IE1-pp65 protein for the generation of epitope-specific T cell immunity. AU - Nguyen, Thi Hoang Oanh. AU - Mifsud, Nicole Andrea. AU - Stewart, Lisbeth A. AU - Rose, Mingus J. AU - Etto, Tamara L. AU - Williamson, Nicholas A. AU - Purcell, Anthony Wayne. AU - Kotsimbos, Tom C. AU - Schwarer, Anthony. PY - 2008. Y1 - 2008. UR - http://www.elsevier.com/locate/yprep. M3 - Article. VL - 61. SP - 22. EP - 30. JO - Protein Expression and Purification. JF - Protein Expression and Purification. SN - 1046-5928. IS - 1. ER - ...
Treatment of invasive adenovirus (Ad) disease in hematopoietic stem cell transplant (SCT) recipients with capsid protein hexon-specific donor T cells is under investigation. We propose that cytotoxic T cells (CTLs) targeted to the late protein hexon may be inefficient in vivo because the early Ad protein E3-19K downregulates HLA class I antigens in infected cells. In this study, CD8+ T cells targeted to highly conserved HLA A2-restricted epitopes from the early regulatory protein DNA polymerase (P-977) and late protein hexon (H-892) were compared in peripheral blood (PB) and tonsils of naturally infected adults. In tonsils, epitope-specific pentamers detected a significantly higher frequency of P-977+CD8+ T cells compared to H-892+CD8+ T cells; this trend was reversed in PB. Tonsil epitope-specific CD8+ T cells expressed IFN-γ and IL-2 but not perforin or TNF-α, whereas PB T cells were positive for IFN-γ, TNF-α, and perforin. Tonsil epitope-specific T cells expressed lymphoid homing marker CCR7 and
Immune monitoring of T cell responses increasingly relies on the use of peptide pools. Peptides, when restricted by the same HLA allele, and presented from within the same peptide pool, can compete for HLA binding sites. What impact such competition has on functional T cell stimulation, however, is not clear. Using a model peptide pool that is comprised of 32 well-defined viral epitopes from Cytomegalovirus, Epstein-Barr virus, and Influenza viruses (CEF peptide pool), we assessed peptide competition in PBMC from 42 human subjects. The magnitude of the peptide pool-elicited CD8 T cell responses was a mean 79% and a median 77% of the sum of the CD8 T cell responses elicited by the individual peptides. Therefore, while the effect of peptide competition was evident, it was of a relatively minor magnitude. By studying the dose-response curves for individual CEF peptides, we show that several of these peptides are present in the CEF-pool at concentrations that are orders of magnitude in excess of what is
easYmer HLA-B*46:01 MHC Tetramers Kit can be used to generate monomers with your choice of peptide and to analyze T-cells by flow cytometry.
A method for updating detecting and loading CD volume indexes from a multiple-CD set to a cumulative volume table contained in a computer memory. The method employs an volume index file on each intermediate CD of the set along with a dual index file feature on the last CD of the set. The second index file on the last CD is a cumulative file of all the index files contained on all the CDs of the set. The cumulative index file on the last CD is compared to the cumulative volume table to generate a list of missing volumes which have not already been loaded into computer memory. The method permits determining whether a given CD is a single CD or a CD that is one of a multiple-CD set by detecting the presence of a second volume index file on the CD.
p286/I-Ag7 tetramer-positive CD4+ T cells from G286 mice delay diabetes transfer. Tetramer-positive and -negative cells were sorted from G286 lymph node cells w
Dear Netters, Does anyone know of any software for the prediction of T-cell epitopes from peptide sequences? I have access to Mac, PC, VAX, SG & UNIX so the program format does not matter. Hope to hear from someone soon! Thanks, Brian Robertson Max-Planck-Institut fuer Biologie Abt. Infektionsbiologie D74 Tuebingen, FRG. Email robertson at mpib-tuebingen.mpg.de ...
CTL recognition and antagonism by naturally occurring p17 variants. Recognition of variant peptides by two donor 008 clones (18 and 20) (a and b) at an ET of 8
PubMed journal article Identification and characterization of a human agonist cytotoxic T-lymphocyte epitope of human prostate-specific antige were found in PRIME PubMed. Download Prime PubMed App to iPhone, iPad, or Android
The proteasome, an essential component of the ATP-dependent proteolytic pathway in eukaryotic cells, is responsible for the degradation of most cellular proteins and is believed to be the main source of MHC class I-restricted antigenic peptides for presentation to CTL. Inhibition of the proteasome by lactacystin or various peptide aldehydes can result in defective Ag presentation, and the pivotal role of the proteasome in Ag processing has become generally accepted. However, recent reports have challenged this observation. Here we examine the processing requirements of two HLA A*0201-restricted epitopes from HIV-1 reverse transcriptase and find that they are produced by different degradation pathways. Presentation of the C-terminal ILKEPVHGV epitope is impaired in ME275 melanoma cells by treatment with lactacystin, and is independent of expression of the IFN-gamma-inducible proteasome beta subunits LMP2 and LMP7. In contrast, both lactacystin treatment and expression of LMP7 induce the presentation of
In diseases with a strong association with an HLA haplotype, identification of relevant T cell epitopes may allow alteration of the pathologic process. In this report we use a reverse immunogenetic approach to predict possible HLA class II-restricted T cell epitopes by using complete pool sequencing data. Data from HLA-DR2(B1*1501), -DR3(B1*0301), -DQ2(A1*0501, B1*0201), and -DQ8(A1*0301, B1*0302) alleles were used by a computer program that searches a candidate protein to predict ligands with a relatively high probability of being processed and presented. This approach successfully identified both known T cell epitopes and eluted single peptides from the parent protein. Furthermore, the program identified ligands from proteins in which the binding motif of the HLA molecule was unable to do so. When the information from the nonbinding N- and C-terminal regions in the pool sequence was removed, the ability to predict several ligands was markedly reduced, particularly for the HLA-DQ alleles. This suggests
The identification of class II binding peptide epitopes from autoimmune disease-related antigens is an essential step in the development of antigen-specific immune modulation therapy. In the case of type 1 diabetes, T cell and B cell reactivity to the autoantigen glutamic acid decarboxylase 65 (GAD65) is associated with disease development in humans and in nonobese diabetic (NOD) mice. In this study, we identify two DRB1*0401-restricted T cell epitopes from human GAD65, 274-286, and 115-127. Both peptides are immunogenic in transgenic mice expressing functional DRB1*0401 MHC class II molecules but not in nontransgenic littermates. Processing of GAD65 by antigen presenting cells (APC) resulted in the formation of DRB1*0401 complexes loaded with either the 274-286 or 115-127 epitopes, suggesting that these naturally derived epitopes may be displayed on APC recruited into pancreatic islets. The presentation of these two T cell epitopes in the islets of DRB1*0401 individuals who are at risk for type 1
Vaccines designed to stimulate CTL should be able to deliver protein antigens to the cytoplasm of host cells for processing and presentation by MHC-I. Many systems have been exploited to accomplish cytoplasmic delivery, including viral and bacterial vectors and DNA vaccines (7, 8, 14, 22, 27, 33, 36). There have also been reports demonstrating that antiviral immunity can be primed in mice vaccinated with a recombinant Bordetella adenylate cyclase toxin incorporating a CTL epitope from LCMV (11, 29, 31); however, the data demonstrated protection only when the recombinant toxin was injected in the presence of an adjuvant, aluminum hydroxide (29). Therefore, it remains unclear whether the antiviral protection was a result of toxin delivery or adjuvant activity. This report describes the use of a nontoxic, truncated form of anthrax toxin as an epitope delivery system without the use of adjuvant.. We demonstrate that protective immunity against a viral pathogen, LCMV, is generated in BALB/c mice ...
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We recently discover a new immune escape mechanism that may help viruses escape from immune detection, which might compromise vaccine efficacy. Viruses that cause chronic infection in human contain higher numbers of T cell epitopes whose TCR-facing amino acids are identical to those of numerous peptides from the human proteome. We postulate that viruses that incorporate such human-like epitopes may exploit host tolerance to avoid or suppress effector responses. In order to predict these human-like epitopes, we developed an immunoinformatics tool, JanusMatrix.. Using JanusMatrix, we have identified T cell epitopes in H7N9 influenza HA protein that are highly conserved with human genome epitopes, and these epitopes possess low immunogenicity, activate natural Tregs and suppress bystander effector T cell responses in vitro. The human like T cell epitopes may contribute to the delayed, low titer of H7N9 hemagglutination inhibiting antibody responses and diminished seroconversion rates that have been ...
The Experimental Analysis of Mutlitple Computationally-Driven Methods for the Deletion of Broadly Distributed T cell Epitopes in a Functional Biotherapeutic Candidate A Thesis Submitted to the Faculty in partial fulfillm ent o f the requirements for the degree of D octor o f Philosophy by Regina Salvat Thayer School o f Engineering D artmouth College Hanover, N ew Hampshire January 4, 2015 Chairman Exam ining Committee: Professor Karl Griswold M em ber Professor M argaret Ackerman M em ber Professor Chris Bailey-Kellogg M emb er___________________________ Professor Lenny M oise F. Jon Kull Dean o f Graduate Studies ...
To our knowledge, this is the first large-scale reverse-genomics study in which the results of a genetic analysis were used to directly inform the selection and subsequent testing of particular viral Ags. Overall, we were able to provide immunological support for 190 HLA-associated polymorphisms in subtype B HIV-1 as being sites of direct T cell recognition in vivo based on ex vivo IFN-γ responses in the appropriate HLA background. This was 58% of the HLA associations tested in the study, representing an increase from only 35% that could have been explained by well-characterized published CD8 T cell epitopes alone, prior to any cellular testing. For nine high-probability epitopes, there was a sufficiently frequent HLA type to show that the most likely HLA restriction of the epitopic response in the cohort matched that of the prediction, and there was sufficient frequency of testing and responses in ≥40% of cases to give the best level of evidence for immunoreactivity. An additional set of ...
Rational design of immunotherapeutics relies on clear knowledge of the immunodominant epitopes of antigens. Current methods for identifying kinetically stable peptide-MHC complexes are in many cases i
Peptides that combine poorly to MHC course We substances elicit low functional avidity Capital t cell reactions often. immune system reactions can become increased towards Capital t cell epitopes with low practical avidity by raising antigen denseness. We also determined a heteroclitic epitope (RCVIFANI) that elicited a Capital t cell response with almost full cross-reactivity with indigenous epitope and proven improved MHC-peptide plethora likened to indigenous S i9000598. Structural and thermal dissolve studies indicated that the Queen600V replacement improved balance of the peptide-MHC complicated without significantly changing the antigenic surface area, causing in cross-reactive Big t cell reactions extremely. Our data high light that improved pMHC Rabbit polyclonal to IL25 complicated screen contributes to heteroclitic epitope effectiveness and explain guidelines for increasing immune system reactions that cross-react with the indigenous epitope. Intro growth and Virus distance both ...
T cells play pivotal roles in shaping host immune responses in infectious diseases, autoimmunity and cancer. The activation of T cells requires immune and growth factor-derived signals. However, alterations in nutrients and metabolic signals tune T cell responses by impinging upon T cell fates and immune functions. In this review, we summarize how key nutrients, including glucose, amino acids and lipids, and their sensors and transporters shape T cell responses. We also briefly discuss regulation of T cell responses by oxygen and energy sensing mechanisms.
Analysis of cytotoxic T cell epitopes in relation to cancer. / Stranzl, Thomas; Brunak, Søren (Main supervisor); Larsen, Mette Voldby (Supervisor).. Kgs. Lyngby : Technical University of Denmark (DTU), 2012. 97 p.. Publication: Research › Ph.D. thesis - Annual report year: 2012 ...
In this study we characterized the CTL response induced in vivo against TS/A mouse adenocarcinoma cells genetically engineered to express different cytokine or costimulatory molecules, i.e., IFN-α, IFN-γ, IL-4, and B7.1. Independent of the molecule introduced, the CTL response elicited was constantly directed against a single immunodominant epitope represented by the AH1 peptide derived from the gp70 product of an endogenous MuLV and corresponding to amino acids 423-431 of the protein (19) . Indeed, tumor rejection was accompanied by increases in a CD8+ T-cell population that was stainable with gp70-specific tetramers; moreover, independent in vitro restimulation of splenocytes from mice that had rejected a primary TS/A tumor challenge with either gp70423-431 peptide or engineered TS/A, which provided the entire antigenic array of the tumor cells, produced a similar large increase in CTLs specifically recognizing the AH1 antigenic epitope. Finally, MLTC lytic activity could be inhibited in an ...
Authors: AI Webb, MA Dunstone, WS Chen, MI Aguilar, QY Chen, H Jackson, L Chang, L Kjer-Nielsen, T Beddoe, J McCluskey, J Rossjohn, AW Purcell
To better understand relationships between CD8+ T-cell specificity and the immune control of human immunodeficiency virus type 1 (HIV-1), we analyzed the role of HLA-B*13, an allele associated with low viremia, in a cohort of 578 C clade-infected individuals in Durban, South Africa. Six novel B*13-restricted cytotoxic T lymphocyte epitopes were defined from analyses of 37 B*13-positive subjects, including three Gag epitopes. These B*13-restricted epitopes contribute to a broad Gag-specific CD8+ response that is associated with the control of viremia. These data are consistent with data from studies of other HLA-class I alleles associated with HIV control that have shown that the targeting of multiple Gag epitopes is associated with relative suppression of viremia.
Despite widespread uses of tetanus toxoid (TT) as a vaccine, model antigen and protein carrier, TT epitopes have been poorly characterized. Herein we defined the human CD4+ T cell epitope repertoire by reevaluation of previously described epitopes and evaluation of those derived from prediction of HLA Class II binding. Forty-seven epitopes were identified following in vitro TT stimulation, with 28 epitopes accounting for 90% of the total response. Despite this diverse range of epitopes, individual responses were associated with only a few immunodominant epitopes, with each donor responding on average to 3 epitopes. For the top 14 epitopes, HLA restriction could be inferred based on HLA typing of the responding donors. HLA binding predictions re-identified the vast majority of known epitopes, and identified 24 additional novel epitopes. With these epitopes, we created a TT epitope pool, which allowed us to characterize TT responses directly ex vivo using a cytokine-independent Activation Induced ...
Allergic diseases represent a major public health issue. Improved understanding of the immunological mechanisms underlying the cause & development of disease, and therapeutic interventions will inform the development and refinement of novel forms of therapy. The McMaster T-cell Epitope Centre (MTEC) uses new epitope-specific tools to determine the frequency and function of T cells reactive with the cat allergen, Fel d 1. These T cells have been shown in our previous studies to play a key role in allergic asthma and the response to immunotherapy.. MTEC will use unique Major Histocompatibility (MHC) class II tetramers containing T cell epitopes of the major cat allergen Fel d 1 in order to characterize allergen-specific T cells before and after intervention with (1) a peptide-based therapeutic vaccine comprised of immunodominant T cell epitopes of Fel d 1, and (2) bronchial (segmental) allergen challenge with cat allergen extract. Two research Projects and two Cores are proposed. The Cores ...
Allergic diseases represent a major public health issue. Improved understanding of the immunological mechanisms underlying the cause & development of disease, and therapeutic interventions will inform the development and refinement of novel forms of therapy. The McMaster T-cell Epitope Centre (MTEC) uses new epitope-specific tools to determine the frequency and function of T cells reactive with the cat allergen, Fel d 1. These T cells have been shown in our previous studies to play a key role in allergic asthma and the response to immunotherapy.. MTEC will use unique Major Histocompatibility (MHC) class II tetramers containing T cell epitopes of the major cat allergen Fel d 1 in order to characterize allergen-specific T cells before and after intervention with (1) a peptide-based therapeutic vaccine comprised of immunodominant T cell epitopes of Fel d 1, and (2) bronchial (segmental) allergen challenge with cat allergen extract. Two research Projects and two Cores are proposed. The Cores ...
The mechanism of LN-specific, Ag-specific Treg enrichment might depend on factors regulating T cell homing to LN, encounter with self-Ag, and their retention in the LN. Homing of naive T cells and Treg to normal LN are known to involve CD62L, CCR7, and the chemokines CCL19 and CCL21 (15). Autoimmune diseases occur in mice deficient in CD62L or CCR7 (16, 17), for which we can now add a potential explanation: the loss of DS-Treg enrichment in regional LN. Treg retention may result from up-regulation of CD69 on Ag-specific Treg that temporarily sequester sphingosine 1-phosphate receptor type 1, which is required for T cell egress from LN (18). Additional mechanisms may involve Treg response to antiapoptotic and/or cellular proliferation signals (19). Constrained by T cell homeostatic mechanisms (20), the number or activity of DS-Treg in the regional LN would be maintained at a threshold 15- to 50-fold greater than those in the nondraining LN.. Additional mechanisms participate in Ag-specific Treg ...
The high diversity of HLA binding preferences has been driven by the sequence diversity of short segments of relevant pathogenic proteins presented by HLA molecules to the immune system. To identify possible commonalities in HLA binding preferences, we quantify these using a novel measure termed "targeting efficiency," which captures the correlation between HLA-peptide binding affinities and the conservation of the targeted proteomic regions. Analysis of targeting efficiencies for 95 HLA class I alleles over thousands of human proteins and 52 human viruses indicates that HLA molecules preferentially target conserved regions in these proteomes, although the arboviral Flaviviridae are a notable exception where nonconserved regions are preferentially targeted by most alleles. HLA-A alleles and several HLA-B alleles that have maintained close sequence identity with chimpanzee homologues target conserved human proteins and DNA viruses such as Herpesviridae and Adenoviridae most efficiently, while all ...
Tetrameric MHC/peptide complexes are important tools for enumerating, phenotyping, and rapidly cloning Ag-specific T cells. It remains however unclear whether they can reliably distinguish between high and low avidity T cell clones. In this report, tetramers with mutated CD8 binding site selectively stain higher avidity human and murine CTL capable of recognizing physiological levels of Ag. Furthermore, we demonstrate that CD8 binding significantly enhances the avidity as well as the stability of interactions between CTL and cognate tetramers. The use of CD8-null tetramers to identify high avidity CTL provides a tool to compare vaccination strategies for their ability to enhance the frequency of high avidity CTL. Using this technique, we show that DNA priming and vaccinia boosting of HHD A2 transgenic mice fail to selectively expand large numbers of high avidity NY-ESO-1(157-165)-specific CTL, possibly due to the large amounts of antigenic peptide delivered by the vaccinia virus. Furthermore,
Population-based vaccine design workflow in KNIME. AlleleFrequency is used to specify the geographical region or population of interest and returns a tab-separated list of HLA alleles with their corresponding occurrence probability within the selected population. This file, together with a FASTA file containing protein sequences, or a file containing peptides is used as input to EpitopePrediction, which generates a file containing the predicted binding affinities of the (generated) peptides and the selected HLA alleles. This file, in turn, is used as input to EpitopeSelection, which selects a user-defined number of epitopes out of the candidate pool and writes these together with other statistics into an output file.?. ...
Characterization of human leukocyte antigen (HLA) class I restricted epitopes derived from viral pathogens is imperative for formulating therapeutic interventions, as well as for vaccine design and monitoring. Sensitive, easy and cost-effective assays that measure the frequency of antigen-specific T lymphocytes are crucial for evaluating and improving vaccines and therapies. This paper reviews the ELISPOT technique that allows for quantifying HIV-specific T lymphocytes at the single cell level from peripheral blood by detection of antigen-induced cytokine secretion. The assay can be used successfully to quantify T cell immune responses in humans infected with different pathogens and to assess T cell immunogenicity of vaccines in phase I/II and III clinical trials. This review focuses on the ELISPOT methodology and discusses how it can be standardized and potentially used by multiple international laboratories attached to clinical trial sites.
The K43R mutation quickly emerged and was rapidly fixed in the viral population after infection in CH0131, suggesting that it was strongly selected in the host. Because no conventional or cryptic T cell responses were detected for the regions containing the K43R mutation and that the Gag protein does not elicit neutralizing antibodies, the strong selection pressure on the K43R mutation could not be from adaptive T and B cell responses. We have shown clearly that strong immunodominant T cell responses exerted the strongest and most rapid selection pressure in our previous study [8]. Using the same approach, we showed that T cell responses to the WF9 epitope were absent or at least below the level of detection in this highly sensitive assay. Therefore, if there were T cell responses targeting the K43R site that were undetectable (and far from immunodominant), it would be difficult to envision how it could exert any significant pressure to select such a rapid escape, with a fitness loss.. T cell ...
T cell responses play an important role in the outcome of HBV and HCV infection, e.g. viral elimination versus persistence. However, multiple mechanisms can lead to the failure of the virus-specific T cell response. These mechanisms include primary T cell failure, T cell exhaustion, the emergence of viral escape mutants, as well as T cell dysfunction. Furthermore, genetic factors such as the individual HLA allele background play an important role in the outcome of infection. Once viral persistence has been established, HBV or HCV infection can progress to liver fibrosis and cirrhosis with an enhanced risk for HCC. Tumor-specific T cells (e.g. AFP-specific T cells) are thought to contribute to cancer control.. The focus of our group is the identification and characterization of virus-specific CD4+ and CD8+ T cell responses during acute and chronic HBV and HCV infection with a special focus on intrahepatic T cell responses as well as the mechanisms of viral persistence (e.g., viral escape, T cell ...
CD8+ T cells dominate the lymphocyte population insynovial fluid in chronic inflammatory arthritis. It is known that theseCD8+ T cells are often clonally or oligoclonally expanded, but theirspecificity and their relevance to the pathogenesis of joint disease hasremained unclear. We found that as many as 15.5% of synovial CD8+ Tcells may be specific for a single epitope from an Epstein-Barr virus lyticcycle protein. The virus-specific T cells within the joint showed increasedexpression of markers of activation and differentiation compared with those inthe periphery, and retained their functional capacity to secreteproinflammatory cytokines on stimulation. These activated, virus-specificCD8+ T cells could therefore interact with synoviocytes, either bycell-cell contact or by a cytokine network, and play a bystanderrole in the maintenance of inflammation in patients with arthritis.