Protection of mice against experimental cryptococcosis by synthesized peptides delivered in glucan particles

The high global burden of cryptococcosis has made development of a protective vaccine a public health priority. We previously demonstrated that a vaccine composed of recombinant Cryptococcus neoformans chitin deacetylase 2 (Cda2) delivered in glucan particles (GPs) protects BALB/c and C57BL/6 mice from an otherwise lethal challenge with a highly virulent C. neoformans strain. An immunoinformatic analysis of Cda2 revealed a peptide sequence predicted to have strong binding to the MHC Class II (MHC II) H2-IAd allele found in BALB/c mice. BALB/c mice vaccinated with GPs containing a 32 amino acid peptide (Cda2-Pep1) that included this strong binding region were protected from cryptococcosis. Protection was lost with GP-based vaccines containing versions of recombinant Cda2 protein and Cda2-Pep1 with mutations predicted to greatly diminish MHC II binding. Cda2 has homology to the three other C. neoformans chitin deacetylases, Cda1, Cda3 and Fpd1, in the high MHC II binding region. GPs loaded with homologous peptides of Cda1, Cda3 and Fpd1 protected BALB/c mice from experimental cryptococcosis, albeit not as robustly as the Cda2-Pep1 vaccine. Finally, seven other peptides were synthesized based on regions in Cda2 predicted to contain promising CD4+ T cell epitopes in BALB/c or C57BL/6 mice. While five peptide vaccines significantly protected BALB/c mice, only one protected C57BL/6 mice. Thus, GP-based vaccines containing a single peptide can protect mice against cryptococcosis. However, given the diversity of human MHC II alleles, a peptide-based Cryptococcus vaccine for use in humans would be challenging and likely need to contain multiple peptide sequences.

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Peptides identified on monocyte-derived dendritic cells: a marker for clinical immunogenicity to FVIII products

Blood Advances ◽

10.1182/bloodadvances.2018030452 ◽

2019 ◽

Vol 3 (9) ◽

pp. 1429-1440 ◽

Cited By ~ 7

Author(s):

Wojciech Jankowski ◽

Yara Park ◽

Joseph McGill ◽

Eugene Maraskovsky ◽

Marco Hofmann ◽

...

Keyword(s):

Dendritic Cells ◽

Mhc Class Ii ◽

Unmet Need ◽

Specific Protein ◽

Proteolytic Processing ◽

T Cell Epitopes ◽

Mhc Ii ◽

Healthy Donors ◽

Recombinant Fviii ◽

Von Willebrand

Abstract The immunogenicity of protein therapeutics is an important safety and efficacy concern during drug development and regulation. Strategies to identify individuals and subpopulations at risk for an undesirable immune response represent an important unmet need. The major histocompatibility complex (MHC)–associated peptide proteomics (MAPPs) assay directly identifies the presence of peptides derived from a specific protein therapeutic on a donor’s MHC class II (MHC-II) proteins. We applied this technique to address several questions related to the use of factor VIII (FVIII) replacement therapy in the treatment of hemophilia A (HA). Although >12 FVIII therapeutics are marketed, most fall into 3 categories: (i) human plasma-derived FVIII (pdFVIII), (ii) full-length (FL)–recombinant FVIII (rFVIII; FL-rFVIII), and (iii) B-domain–deleted rFVIII. Here, we investigated whether there are differences between the FVIII peptides found on the MHC-II proteins of the same individual when incubated with these 3 classes. Based on several observational studies and a prospective, randomized, clinical trial showing that the originally approved rFVIII products may be more immunogenic than the pdFVIII products containing von Willebrand factor (VWF) in molar excess, it has been hypothesized that the pdFVIII molecules yield/present fewer peptides (ie, potential T-cell epitopes). We have experimentally tested this hypothesis and found that dendritic cells from HA patients and healthy donors present fewer FVIII peptides when administered pdFVIII vs FL-rFVIII, despite both containing the same molar VWF excess. Our results support the hypothesis that synthesis of pdFVIII under physiological conditions could result in reduced heterogeneity and/or subtle differences in structure/conformation which, in turn, may result in reduced FVIII proteolytic processing relative to FL-rFVIII.

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Predict the Strong Binding Ability Polypeptide of Human α-Enolase with the HLA-DRB1 * 0401

Applied Mechanics and Materials ◽

10.4028/www.scientific.net/amm.380-384.4353 ◽

2013 ◽

Vol 380-384 ◽

pp. 4353-4358

Author(s):

Rui Jie ◽

Quan Zhou ◽

Jin Song Wang ◽

Yun He Liang ◽

Ting Ting Liao ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Molecular Dynamics ◽

Mhc Class Ii ◽

Structural Model ◽

Three Dimensional ◽

Prediction Method ◽

T Cell Epitopes ◽

Binding Ability ◽

Strong Binding ◽

Chain Conformations

Human α-enolase (ENO1), an evolutionarily conserved and multifunctional protein, is a target self-antigen of rheumatoid arthritis (RA). Rheumatoid arthritis (RA) is genetically associated with MHC class II molecules, such as DRB1*0101, DRB1*0401 and DRB1*0404 allele. Among these DRB1 alleles, DRB1*0401 show the most correlation with RA. However, strong binding ability polypeptide of ENO1 with HLA-DRB1*0401 is still largely unknown. In this study, we used NetMHCII prediction method to predict the strong binding ability polypeptide with HLA-DRB1*0401. Among the 434 predicted fragment peptide, ENO1129-141: PLYRHIADLAGNS showed strong binding with HLA-DR4 and peptide ENO1281-293 KSFIKDYPVVSIE is the second candidate peptide. Based on these result, we choosed EON1129-141 and EON1281-293 polypeptides to do the molecular modeling, and used the molecular dynamics to optimize the three-dimensional structural model. The molecular dynamics results showed that ENO1129-141: PLYRHIADLAGNS and ENO1281-293: KSFIKDYPVVSIE have strong binding ability with HLA-DR4* 0401. In the shared epitope, both ENO1129-141and ENO1281-293 have the very near distance 3.15Å and 3.10Å with K71 of the β1 chain. The main-chain conformations of ENO1129-141 sit more deeply with β1 chain. All together, results indicated that ENO1129-141 and ENO1281-293 bind strong with HLA-DR4 and would be potential T cell epitopes of human α-enolase that induced RA.

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Scouting the Receptor Binding Domain of COVID-19: A Comprehensive Immunoinformatics Inquisition

10.21203/rs.3.rs-25501/v1 ◽

2020 ◽

Author(s):

Zaira Rehman ◽

Ammad Fahim ◽

Muhammad Faraz Bhatti

Keyword(s):

T Cell ◽

Receptor Binding ◽

Binding Domain ◽

Peptide Sequence ◽

Preventive Strategy ◽

Receptor Binding Domain ◽

T Cell Epitopes ◽

Mhc I ◽

Mhc Ii ◽

Potential Vaccine

Abstract The December of 2019 witnessed emergence of worldwide outbreak by a novel strain of coronavirus termed COVID-19 with sequence similarity of overall 96.2% with BatCoV RaTG13 (coronavirus isolated from bat) and 94% sequence identity with Severe Acute respiratory syndrome Virus (SARS-CoV) that resulted in outbreak in 2002-2003. There is no therapeutic or preventive strategy like vaccine developed so far to overcome infection.The receptor binding domain (RBD) of COVID-19 for any potential vaccine epitopes were explored. The structure of RBD of COVID-19, BatCoV RaTG13 and bACE2 were chalked through homology modeling followed by molecular docking and structural validation. A comprehensive immunoinformatics approach mapped conserved peptide sequence on COVID-19 RBD for their B-, Helper T- & Cytotoxic T-cell epitope profile. The recognized epitopes were further studied and validated for their docking interaction with MHC-I and MHC-II alleles. Through immune-informatics approaches the study identified conserved B- and T-cell epitopes in RBD. The B-cell epitopes lying within the receptor binding motif, LFRKSN and SYGFQPT l were found to be highly antigenic. Among T-cell epitopes, the epitope CVADYSVLY and FTNVYADSF were antigenic and exhibited affinity for maximum number of MHC-I alleles. The T cell epitopes YRLFRKSNL, VYAWNRKRI displayed affinity for maximum number of MHC-II alleles. The docking analysis of the epitopes with MHC proteins revealed strong interactions of T-cell epitopes with MHC-I and MHC-II alleles. The overlapping epitope among B- and T-cells was YRLFRKSNL. The deployment of these epitopes in potential vaccine against COVID-19 may help in sweeping the COVID-19 infectious spread.

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Synaptic Clusters of MHC Class II Molecules Induced on DCs by Adhesion Molecule–mediated Initial T-Cell Scanning

Molecular Biology of the Cell ◽

10.1091/mbc.e05-01-0005 ◽

2005 ◽

Vol 16 (7) ◽

pp. 3314-3322 ◽

Cited By ~ 54

Author(s):

Hortensia de la Fuente ◽

María Mittelbrunn ◽

Lorena Sánchez-Martín ◽

Miguel Vicente-Manzanares ◽

Amalia Lamana ◽

...

Keyword(s):

T Cells ◽

Mhc Class Ii ◽

Class Ii ◽

Regulatory Pathway ◽

Immune Synapse ◽

Mhc Ii ◽

Cytoskeleton Reorganization ◽

Adhesive Contacts ◽

Enhance Antigen Presentation ◽

Mhc Class Ii Molecules

Initial adhesive contacts between T lymphocytes and dendritic cells (DCs) facilitate recognition of peptide-MHC complexes by the TCR. In this report, we studied the dynamic behavior of adhesion and Ag receptors on DCs during initial contacts with T-cells. Adhesion molecules LFA-1- and ICAM-1,3-GFP as well as MHC class II-GFP molecules were very rapidly concentrated at the DC contact area. Binding of ICAM-3, and ICAM-1 to a lesser extent, to LFA-1 expressed by mature but not immature DC, induced MHC-II clustering into the immune synapse. Also, ICAM-3 binding to DC induced the activation of the Vav1-Rac1 axis, a regulatory pathway involved in actin cytoskeleton reorganization, which was essential for MHC-II clustering on DCs. Our results support a model in which ICAM-mediated MHC-II clustering on DC constitutes a priming mechanism to enhance antigen presentation to T-cells.

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Major Histocompatibility Complex Class II+ Invariant Chain Negative Breast Cancer Cells Present Unique Peptides that Activate Tumor-specific T Cells from Breast Cancer Patients

Molecular & Cellular Proteomics ◽

10.1074/mcp.m112.019232 ◽

2012 ◽

Vol 11 (11) ◽

pp. 1457-1467 ◽

Cited By ~ 12

Author(s):

Olesya Chornoguz ◽

Alexei Gapeev ◽

Michael C. O'Neill ◽

Suzanne Ostrand-Rosenberg

Keyword(s):

Breast Cancer ◽

T Cells ◽

Cancer Cells ◽

Cancer Patients ◽

Mhc Class Ii ◽

Breast Cancer Cells ◽

Class Ii ◽

Breast Cancer Patients ◽

Mhc Ii ◽

Peptide Loading

The major histocompatibility complex (MHC) class II-associated Invariant chain (Ii) is present in professional antigen presenting cells where it regulates peptide loading onto MHC class II molecules and the peptidome presented to CD4+ T lymphocytes. Because Ii prevents peptide loading in neutral subcellular compartments, we reasoned that Ii− cells may present peptides not presented by Ii+ cells. Based on the hypothesis that patients are tolerant to MHC II-restricted tumor peptides presented by Ii+ cells, but will not be tolerant to novel peptides presented by Ii− cells, we generated MHC II vaccines to activate cancer patients' T cells. The vaccines are Ii− tumor cells expressing syngeneic HLA-DR and the costimulatory molecule CD80. We used liquid chromatography coupled with mass spectrometry to sequence MHC II-restricted peptides from Ii+ and Ii− MCF10 human breast cancer cells transfected with HLA-DR7 or the MHC Class II transactivator CIITA to determine if Ii− cells present novel peptides. Ii expression was induced in the HLA-DR7 transfectants by transfection of Ii, and inhibited in the CIITA transfectants by RNA interference. Peptides were analyzed and binding affinity predicted by artificial neural net analysis. HLA-DR7-restricted peptides from Ii− and Ii+ cells do not differ in size or in subcellular location of their source proteins; however, a subset of HLA-DR7-restricted peptides of Ii− cells are not presented by Ii+ cells, and are derived from source proteins not used by Ii+ cells. Peptides from Ii− cells with the highest predicted HLA-DR7 binding affinity were synthesized, and activated tumor-specific HLA-DR7+ human T cells from healthy donors and breast cancer patients, demonstrating that the MS-identified peptides are bonafide tumor antigens. These results demonstrate that Ii regulates the repertoire of tumor peptides presented by MHC class II+ breast cancer cells and identify novel immunogenic MHC II-restricted peptides that are potential therapeutic reagents for cancer patients.

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Epitope-Based Peptide Vaccine Against Fructose-Bisphosphate Aldolase of Madurella mycetomatis Using Immunoinformatics Approaches

Bioinformatics and Biology Insights ◽

10.1177/1177932218809703 ◽

2018 ◽

Vol 12 ◽

pp. 117793221880970 ◽

Cited By ~ 4

Author(s):

Arwa A Mohammed ◽

Ayman MH ALnaby ◽

Solima M Sabeel ◽

Fagr M AbdElmarouf ◽

Amina I Dirar ◽

...

Keyword(s):

B Cell ◽

Binding Affinity ◽

Mhc Class Ii ◽

Bacterial Infections ◽

Peptide Vaccine ◽

Fructose Bisphosphate ◽

Mhc I ◽

Strong Binding ◽

Fructose Bisphosphate Aldolase ◽

Madurella Mycetomatis

Background: Mycetoma is a distinct body tissue destructive and neglected tropical disease. It is endemic in many tropical and subtropical countries. Mycetoma is caused by bacterial infections ( actinomycetoma) such as Streptomyces somaliensis and Nocardiae or true fungi ( eumycetoma) such as Madurella mycetomatis. To date, treatments fail to cure the infection and the available marketed drugs are expensive and toxic upon prolonged usage. Moreover, no vaccine was prepared yet against mycetoma. Aim: The aim of this study is to predict effective epitope-based vaccine against fructose-bisphosphate aldolase enzymes of M. mycetomatis using immunoinformatics approaches. Methods and materials: Fructose-bisphosphate aldolase of M. mycetomatis sequence was retrieved from NCBI. Different prediction tools were used to analyze the nominee’s epitopes in Immune Epitope Database for B-cell, T-cell MHC class II and class I. Then the proposed peptides were docked using Autodock 4.0 software program. Results and conclusions: The proposed and promising peptides KYLQ show a potent binding affinity to B-cell, FEYARKHAF with a very strong binding affinity to MHC I alleles and FFKEHGVPL that shows a very strong binding affinity to MHC II and MHC I alleles. This indicates a strong potential to formulate a new vaccine, especially with the peptide FFKEHGVPL which is likely to be the first proposed epitope-based vaccine against fructose-bisphosphate aldolase of M. mycetomatis. This study recommends an in vivo assessment for the most promising peptides especially FFKEHGVPL.

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Human TCR-MHC coevolution after divergence from mice includes increased nontemplate-encoded CDR3 diversity

Journal of Experimental Medicine ◽

10.1084/jem.20161784 ◽

2017 ◽

Vol 214 (11) ◽

pp. 3417-3433 ◽

Cited By ~ 8

Author(s):

Xiaojing Chen ◽

Lucia Poncette ◽

Thomas Blankenstein

Keyword(s):

T Cells ◽

T Cell ◽

Mhc Class Ii ◽

Cell Receptor ◽

Mhc Molecules ◽

Mhc Ii ◽

Cdr3 Length ◽

Tcr Repertoire ◽

Cell Diversity ◽

Antigen Presenting

For thymic selection and responses to pathogens, T cells interact through their αβ T cell receptor (TCR) with peptide–major histocompatibility complex (MHC) molecules on antigen-presenting cells. How the diverse TCRs interact with a multitude of MHC molecules is unresolved. It is also unclear how humans generate larger TCR repertoires than mice do. We compared the TCR repertoire of CD4 T cells selected from a single mouse or human MHC class II (MHC II) in mice containing the human TCR gene loci. Human MHC II yielded greater thymic output and a more diverse TCR repertoire. The complementarity determining region 3 (CDR3) length adjusted for different inherent V-segment affinities to MHC II. Humans evolved with greater nontemplate-encoded CDR3 diversity than did mice. Our data, which demonstrate human TCR–MHC coevolution after divergence from rodents, explain the greater T cell diversity in humans and suggest a mechanism for ensuring that any V–J gene combination can be selected by a single MHC II.

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Lymph node stromal cells constrain immunity via MHC class II self-antigen presentation

eLife ◽

10.7554/elife.04433 ◽

2014 ◽

Vol 3 ◽

Cited By ~ 45

Author(s):

Antonio P Baptista ◽

Ramon Roozendaal ◽

Rogier M Reijmers ◽

Jasper J Koning ◽

Wendy W Unger ◽

...

Keyword(s):

T Cells ◽

Lymph Node ◽

Antigen Presentation ◽

Mhc Class Ii ◽

Cd8 T Cells ◽

Stromal Cells ◽

Transplant Rejection ◽

Mhc Ii ◽

Self Antigen ◽

Lymph Node Stromal Cells

Non-hematopoietic lymph node stromal cells shape immunity by inducing MHC-I-dependent deletion of self-reactive CD8+ T cells and MHC-II-dependent anergy of CD4+ T cells. In this study, we show that MHC-II expression on lymph node stromal cells is additionally required for homeostatic maintenance of regulatory T cells (Tregs) and maintenance of immune quiescence. In the absence of MHC-II expression in lymph node transplants, i.e. on lymph node stromal cells, CD4+ as well as CD8+ T cells became activated, ultimately resulting in transplant rejection. MHC-II self-antigen presentation by lymph node stromal cells allowed the non-proliferative maintenance of antigen-specific Tregs and constrained antigen-specific immunity. Altogether, our results reveal a novel mechanism by which lymph node stromal cells regulate peripheral immunity.

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MPYS, a Novel Membrane Tetraspanner, Is Associated with Major Histocompatibility Complex Class II and Mediates Transduction of Apoptotic Signals

Molecular and Cellular Biology ◽

10.1128/mcb.00640-08 ◽

2008 ◽

Vol 28 (16) ◽

pp. 5014-5026 ◽

Cited By ~ 243

Author(s):

Lei Jin ◽

Paul M. Waterman ◽

Karen R. Jonscher ◽

Cindy M. Short ◽

Nichole A. Reisdorph ◽

...

Keyword(s):

Major Histocompatibility Complex ◽

Mhc Class Ii ◽

Cell Activation ◽

Cytoplasmic Tail ◽

Class Ii ◽

Antigenic Peptides ◽

Major Histocompatibility ◽

Mhc Ii ◽

Histocompatibility Complex ◽

Death Signals

ABSTRACT Although the best-defined function of type II major histocompatibility complex (MHC-II) is presentation of antigenic peptides to T lymphocytes, these molecules can also transduce signals leading alternatively to cell activation or apoptotic death. MHC-II is a heterodimer of two transmembrane proteins, each containing a short cytoplasmic tail that is dispensable for transduction of death signals. This suggests the function of an undefined MHC-II-associated transducer in signaling the death response. Here we describe a novel plasma membrane tetraspanner (MPYS) that is associated with MHC-II and mediates its transduction of death signals. MPYS is unusual among tetraspanners in containing an extended C-terminal cytoplasmic tail (∼140 amino acids) with multiple embedded signaling motifs. MPYS is tyrosine phosphorylated upon MHC-II aggregation and associates with inositol lipid and tyrosine phosphatases. Finally, MHC class II-mediated cell death signaling requires MPYS-dependent activation of the extracellular signal-regulated kinase signaling pathway.

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