scholarly journals NetCleave: an open-source algorithm for predicting C-terminal antigen processing for MHC-I and MHC-II

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Pep Amengual-Rigo ◽  
Victor Guallar
Keyword(s):  
Open Source ◽  
Antigen Processing ◽  
High Accuracy ◽  
Biological Processes ◽  
Mhc I ◽  
Mhc Ii ◽  
Prediction Tools ◽  
Immunogenic Peptides ◽  
Physicochemical Descriptors ◽  
Peptide Presentation

AbstractAntigens presented on the cell surface have been subjected to multiple biological processes. Among them, C-terminal antigen processing constitutes one of the main bottlenecks of the peptide presentation pathways, as it delimits the peptidome that will be subjected downstream. Here, we present NetCleave, an open-source and retrainable algorithm for the prediction of the C-terminal antigen processing for both MHC-I and MHC-II pathways. NetCleave architecture consists of a neural network trained on 46 different physicochemical descriptors of the cleavage site amino acids. Our results demonstrate that prediction of C-terminal antigen processing achieves high accuracy on MHC-I (AUC of 0.91), while it remains challenging for MHC-II (AUC of 0.66). Moreover, we evaluated the performance of NetCleave and other prediction tools for the evaluation of four independent immunogenicity datasets (H2-Db, H2-Kb, HLA-A*02:01 and HLA-B:07:02). Overall, we demonstrate that NetCleave stands out as one of the best algorithms for the prediction of C-terminal processing, and we provide one of the first evidence that C-terminal processing predictions may help in the discovery of immunogenic peptides.

scholarly journals HLA-class II specificity assessed by high-density peptide microarray interactions

2020 ◽  
Author(s):  
Thomas Osterbye ◽  
Morten Nielsen ◽  
Nadine L. Dudek ◽  
Sri H. Ramarathinam ◽  
Anthony W. Purcell ◽  
...  
Keyword(s):  
Mhc Class Ii ◽  
Cell Epitope ◽  
Class Ii ◽  
High Density ◽  
Class I Mhc ◽  
Mhc I ◽  
Peptide Epitopes ◽  
Mhc Ii ◽  
Prediction Tools ◽  
Binding Data

AbstractThe ability to predict and/or identify MHC binding peptides is an essential component of T cell epitope discovery; something that ultimately should benefit the development of vaccines and immunotherapies. In particular, MHC class I (MHC-I) prediction tools have matured to a point where accurate selection of optimal peptide epitopes is possible for virtually all MHC-I allotypes; in comparison, current MHC class II (MHC-II) predictors are less mature. Since MHC-II restricted CD4+ T cells control and orchestrate most immune responses, this shortcoming severely hampers the development of effective immunotherapies. The ability to generate large panels of peptides and subsequently large bodies of peptide-MHC-II interaction data is key to the solution of this problem; a solution that also will support the improvement of bioinformatics predictors, which critically relies on the availability of large amounts of accurate, diverse and representative data. Here, we have used recombinant HLA-DRB1*01:01 and HLA-DRB1*03:01 molecules to interrogate high-density peptide arrays, in casu containing 70,000 random peptides in triplicates. We demonstrate that the binding data acquired contains systematic and interpretable information reflecting the specificity of the HLA-DR molecules investigated. Collectively, with a cost per peptide reduced to a few cents combined with the flexibility of recombinant HLA technology, this poses an attractive strategy to generate vast bodies of MHC-II binding data at an unprecedented speed and for the benefit of generating peptide-MHC-II binding data as well as improving MHC-II prediction tools.

scholarly journals Hepatic Stellate Cells and Hepatocytes as Liver Antigen-Presenting Cells during B. abortus Infection

Pathogens ◽  
2020 ◽  
Vol 9 (7) ◽  
pp. 527
Author(s):  
Paula Constanza Arriola Benitez ◽  
Ayelén Ivana Pesce Viglietti ◽  
María Mercedes Elizalde ◽  
Guillermo Hernán Giambartolomei ◽  
Jorge Fabián Quarleri ◽  
...  
Keyword(s):  
Antigen Presentation ◽  
Hepatic Stellate Cells ◽  
Antigen Processing ◽  
Stellate Cells ◽  
Class Ii Transactivator ◽  
Mhc I ◽  
Mhc Ii ◽  
Antigen Presenting ◽  
Antigen Processing And Presentation ◽  
Culture Supernatants

In Brucellosis, the role of hepatic stellate cells (HSCs) in the induction of liver fibrosis has been elucidated recently. Here, we study how the infection modulates the antigen-presenting capacity of LX-2 cells. Brucella abortus infection induces the upregulation of class II transactivator protein (CIITA) with concomitant MHC-I and -II expression in LX-2 cells in a manner that is independent from the expression of the type 4 secretion system (T4SS). In concordance, B. abortus infection increases the phagocytic ability of LX-2 cells and induces MHC-II-restricted antigen processing and presentation. In view of the ability of B. abortus-infected LX-2 cells to produce monocyte-attracting factors, we tested the capacity of culture supernatants from B. abortus-infected monocytes on MHC-I and –II expression in LX-2 cells. Culture supernatants from B. abortus-infected monocytes do not induce MHC-I and -II expression. However, these supernatants inhibit MHC-II expression induced by IFN-γ in an IL-10 dependent mechanism. Since hepatocytes constitute the most abundant epithelial cell in the liver, experiments were conducted to determine the contribution of these cells in antigen presentation in the context of B. abortus infection. Our results indicated that B. abortus-infected hepatocytes have an increased MHC-I expression, but MHC-II levels remain at basal levels. Overall, B. abortus infection induces MHC-I and -II expression in LX-2 cells, increasing the antigen presentation. Nevertheless, this response could be modulated by resident or infiltrating monocytes/macrophages.

scholarly journals The Global Architecture Shaping the Heterogeneity and Tissue-Dependency of the MHC Class I Immunopeptidome is Evolutionarily Conserved

2020 ◽  
Author(s):  
Peter Kubiniok ◽  
Ana Marcu ◽  
Leon Bichmann ◽  
Leon Kuchenbecker ◽  
Heiko Schuster ◽  
...  
Keyword(s):  
T Cell ◽  
Antigen Processing ◽  
Global Analysis ◽  
Primary Source ◽  
Independent Manner ◽  
Mhc I ◽  
Mhc Ii ◽  
Mouse Tissues ◽  
High Level

ABSTRACTUnderstanding the molecular principles that govern the composition of the mammalian MHC-I immunopeptidome (MHC-Ii) across different primary tissues is fundamentally important to predict how T cell respond in different contexts in vivo. Here, we performed a global analysis of the mammalian MHC-Ii from 29 and 19 primary human and mouse tissues, respectively. First, we observed that different HLA-A, -B and -C allotypes do not contribute evenly to the global composition of the MHC-Ii across multiple human tissues. Second, we found that peptides that are presented in a tissue-dependent and -independent manner share very distinct properties. Third, we discovered that proteins that were evolutionarily hyperconserved represent the primary source of the MHC-Ii at the organism-wide scale. Finally, we uncovered a remarkable antigen processing and presentation network that may drive the high level of heterogeneity of the MHC-Ii across different tissues in mammals. This study opens up new avenues toward a system-wide understanding of antigen presentation in vivo and may serve as ground work to understand tissue-dependent T cell responses in autoimmunity, infectious diseases and cancer.

scholarly journals Transcriptome Analysis Shows That IFN-I Treatment and Concurrent SAV3 Infection Enriches MHC-I Antigen Processing and Presentation Pathways in Atlantic Salmon-Derived Macrophage/Dendritic Cells

Viruses ◽  
2019 ◽  
Vol 11 (5) ◽  
pp. 464 ◽  
Author(s):  
Cheng Xu ◽  
Øystein Evensen ◽  
Hetron Mweemba Munang’andu
Keyword(s):  
Atlantic Salmon ◽  
Immune Responses ◽  
Transcriptome Analysis ◽  
Antigen Processing ◽  
Type I ◽  
Adaptive Immune Responses ◽  
Mhc I ◽  
Mhc Ii ◽  
Adaptive Immune ◽  
Antigen Processing And Presentation

Type I interferons (IFNs) have been shown to play an important role in shaping adaptive immune responses in addition to their antiviral properties in immune cells. To gain insight into the impact of IFN-I-induced pathways involved in early adaptive immune responses, i.e., antigen-presenting pathways, in an Atlantic salmon-derived (Salmo salar L.) macrophage cell line (TO-cells), we used a comparative de novo transcriptome analysis where cells were treated with IFN-I or kept untreated and concurrently infected with salmonid alphavirus subtype 3 (SAV3). We found that concurrent treatment of TO-cells with IFN-I and SAV3 infection (SAV3/IFN+) significantly enriched the major histocompatibility complex class I (MHC-I) pathway unlike the non-IFN-I treated TO-cells (SAV3/IFN−) that had lower expression levels of MHC-I pathway-related genes. Genes such as the proteasomal activator (PA28) and β-2 microglobulin (β2M) were only differentially expressed in the SAV3/IFN+ cells and not in the SAV3/IFN− cells. MHC-I pathway genes like heat shock protein 90 (Hsp90), transporter of antigen associated proteins (TAPs) and tapasin had higher expression levels in the SAV3/IFN+ cells than in the SAV3/IFN− cells. There were no MHC-II pathway-related genes upregulated in SAV3/IFN+-treated cells, and cathepsin S linked to the degradation of endosomal antigens in the MHC-II pathway was downregulated in the SAV3/IFN− cells. Overall, our findings show that concurrent IFN-I treatment of TO-cells and SAV3 infection enriched gene expression linked to the MHC-I antigen presentation pathway. Data presented indicate a role of type I IFNs in strengthening antigen processing and presentation that may facilitate activation particularly of CD8+ T-cell responses following SAV3 infection, while SAV3 infection alone downplayed MHC-II pathways.

scholarly journals Intracellular mechanisms responsible for exercise-induced suppression of macrophage antigen presentation

2000 ◽  
Vol 88 (2) ◽  
pp. 804-810 ◽  
Author(s):  
M. A. Ceddia ◽  
E. W. Voss ◽  
J. A. Woods
Keyword(s):  
Antigen Presentation ◽  
Antigen Processing ◽  
Day Treatment ◽  
Surface Expression ◽  
Exhaustive Exercise ◽  
Exercise Stress ◽  
Cell Surface Expression ◽  
Mhc Ii ◽  
Immunogenic Peptides ◽  
Exercise Induced

In a previous study, we demonstrated that exhaustive exercise suppressed peritoneal macrophage antigen presentation (AP). In this study, we explored the intracellular mechanism(s) responsible for this suppression. Pathogen-free male BALB/c mice (8 ± 2 wk) were randomly assigned to either home cage control (HCC) or exhaustive exercise stress (Exh, 18–30 m/min for 3 h/day) treatment groups. The mice underwent treatments for a period of 4 days during induced peritoneal thioglycollate inflammation. Elicited macrophages were harvested, purified, and incubated with chicken ovalbumin (C-Ova, 2.5 and 10 mg/ml) for 18 h. After macrophages were washed, they were cocultured with C-Ova-specific T cells for 48 h at which time the supernates were harvested and analyzed via ELISA for interleukin (IL)-2 as an indication of macrophage AP. There was no significant ( P > 0.05) difference in macrophage AP between cells fixed with paraformaldehyde vs. those that remained unfixed, suggesting that Exh did not affect production of soluble factors influencing macrophage AP (i.e., IL-1, IL-4, PGE2). The ability of macrophages to generate C-Ova immunogenic peptides was analyzed using FITC-labeled C-Ova, which shows fluorescence only when degraded intracellularly. There was a significant (∼20%, P< 0.05) suppression in fluorescence in the Exh compared with HCC, indicating a possible defect in the ability of macrophages from Exh to degrade C-Ova into immunogenic peptides. Macrophages were also incubated with C-Ova immunogenic peptide in a manner identical to that for native C-Ova. We found a similar suppression (∼22–38%, P < 0.05) in macrophage AP using a C-Ova peptide when compared with native C-Ova in the Exh group, indicating reduced major histocompatibility complex (MHC) II loading and/or C-Ova-MHC II complex cell surface expression. In conclusion, these data indicate an intracellular defect in the macrophage antigen processing pathway induced by Exh.

Luminal antigens access late endosomes of intestinal epithelial cells enriched in MHC I and MHC II molecules: in vivo study in Crohn's ileitis

2007 ◽  
Vol 293 (4) ◽  
pp. G798-G808 ◽  
Author(s):  
Gheorghe Hundorfean ◽  
Klaus-Peter Zimmer ◽  
Stephan Strobel ◽  
Andreas Gebert ◽  
Diether Ludwig ◽  
...  
Keyword(s):  
T Cells ◽  
Epithelial Cells ◽  
Antigen Processing ◽  
Intestinal Epithelial Cells ◽  
Intestinal Epithelial ◽  
Mhc I ◽  
Mhc Ii ◽  
Late Endosomes ◽  
Early Endosomes

In contrast to healthy conditions, intestinal epithelial cells (IECs) stimulate proinflammatory CD4+and CD8+T cells during Crohn's disease (CD). The underlying regulatory mechanisms remain unknown. Here we investigated the epithelial expression of major histocompatibility complex (MHC) I and MHC II and its interference with endocytic pathways, in vivo. During ileoscopy, ovalbumin (OVA) was sprayed onto ileal mucosa of CD patients (ileitis and remission) and controls. The epithelial traffic of OVA and MHC I/II pathways were studied in biopsies using fluorescence and electron microscopy. We found MHC I and MHC II to accumulate within multivesicular late endosomes (MVLE) of IECs. Faint labeling for these molecules was seen in early endosomes and lysosomes. MVLE were entered by OVA 10 min after exposure. Exosomes carrying MHC I, MHC II, and OVA were detected in intercellular spaces of the epithelium. OVA trafficking and labeling patterns for MHC I and MHC II in IECs showed no differences between CD patients and controls. Independent of inflammatory stimuli, MHC I and MHC II pathways intersect MVLE in IECs, which were efficiently targeted by luminal antigens. Similar to MHC II-enriched compartments in professional antigen presenting cells, these MVLE might be critically involved in MHC I- and MHC II-related antigen processing in IECs and the source of epithelial-released exosomes. The access of luminal antigens to MHC I in MVLE might indicate that the presentation of exogenous antigens by IECs must not be restricted to MHC II but might also occur as “cross-presentation” via MHC I to CD8+T cells.

823 CD4 T cells are essential for an anti-tumor effect in a B78 murine melanoma tumor model

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A873-A873
Author(s):  
Arika Feils ◽  
Mackenzie Heck ◽  
Anna Hoefges ◽  
Peter Carlson ◽  
Luke Zangl ◽  
...  
Keyword(s):  
T Cells ◽  
Tumor Growth ◽  
Cd4 T Cells ◽  
Tumor Response ◽  
Immune Cell ◽  
Cd8 T Cell ◽  
Mhc I ◽  
Mhc Ii ◽  
Flow Cytometric

BackgroundMice bearing B78 melanoma tumors can be cured using an in situ vaccine (ISV) regimen that includes radiation (RT) together with immunocytokine (tumor-targeting mAb conjugated to IL-2). B78 melanoma cells, derived from B16 cells, express minimal to no MHC-I but express MHC-II upon IFN-g/TNF-a stimulation. Although B78 cells are primarily MHC-I-deficient, an increased CD8 T cell infiltration into the tumor microenvironment (TME) has been shown following ISV.1 To further investigate the potential role of specific immune cell lineages in the B78 anti-tumor response to ISV, immune subset depletion studies and flow cytometric analyses were performed.MethodsC57BL/6 mice bearing B78 tumors were depleted of immune cell subsets with mAbs (anti-CD4, anti-CD8, anti-NK1.1, or Rat IgG control) for 3 weeks during the course of treatment. Treatment groups included no treatment, RT (12 Gy), or ISV (RT D0 and immunocytokine D5-D9). 6 mice/group (repeated three times) were followed for survival/tumor growth, and flow cytometry studies included 4 mice/group, sacrificed on D8 and D13 following the start of ISV.ResultsMice depleted of CD4 T cells during the course of ISV showed a significant reduction of anti-tumor effect as compared to mice treated with ISV/Rat IgG (pConclusionsThese studies suggest that CD4 T cells are essential for an anti-tumor response in the B78 melanoma model. In vivo depletion data show that CD4 T cells, but not CD8 or NK cells, are required for a decrease in tumor growth via ISV. Flow cytometric analyses suggest an interplay between CD4 and CD8 T cells as indicated by a decrease in CD8/IFN-g expression following ISV in the absence of CD4 T cells. The role that MHC-I and MHC-II expression plays in this CD4/CD8 T cell anti-tumor response is under investigation. In future studies, B78 melanoma may serve as a critical syngeneic model for development of more effective immunotherapy treatment regimens.Ethics ApprovalAll animal experiments were performed in accordance with protocols approved by Animal Care and Use Committees of the University of Wisconsin-Madison.ReferenceMorris Z, Guy E, Francis D, et al. In situ tumor vaccination by combining local radiation and tumor-specific antibody or immunocytokine treatments. Cancer Res 2016;76(13):3929-3941.

scholarly journals High Levels of a Major Histocompatibility Complex II–Self Peptide Complex on Dendritic Cells from the T Cell Areas of Lymph Nodes

1997 ◽  
Vol 186 (5) ◽  
pp. 665-672 ◽  
Author(s):  
Kayo Inaba ◽  
Maggie Pack ◽  
Muneo Inaba ◽  
Hiraki Sakuta ◽  
Frank Isdell ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
T Cell ◽  
Lymph Nodes ◽  
Mhc I ◽  
Peptide Complex ◽  
Mhc Ii ◽  
Histocompatibility Complex ◽  
Peripheral Lymph ◽  
Free Media ◽  
Very High

T lymphocytes recirculate continually through the T cell areas of peripheral lymph nodes. During each passage, the T cells survey the surface of large dendritic cells (DCs), also known as interdigitating cells. However, these DCs have been difficult to release from the lymph node. By emphasizing the use of calcium-free media, as shown by Vremec et al. (Vremec, D., M. Zorbas, R. Scollay, D.J. Saunders, C.F. Ardavin, L. Wu, and K. Shortman. 1992. J. Exp. Med. 176:47–58.), we have been able to release and enrich DCs from the T cell areas. The DCs express the CD11c leukocyte integrin, the DEC-205 multilectin receptor for antigen presentation, the intracellular granule antigens which are recognized by monoclonal antibodies M342, 2A1, and MIDC-8, very high levels of MHC I and MHC II, and abundant accessory molecules such as CD40, CD54, and CD86. When examined with the Y-Ae monoclonal which recognizes complexes formed between I-Ab and a peptide derived from I-Eα, the T cell area DCs expressed the highest levels. The enriched DCs also stimulated a T-T hybridoma specific for this MHC II–peptide complex, and the hybridoma underwent apoptosis. Therefore DCs within the T cell areas can be isolated. Because they present very high levels of self peptides, these DCs should be considered in the regulation of self reactivity in the periphery.

scholarly journals Preserved MHC-II antigen processing and presentation function in chronic HCV infection

2011 ◽  
Vol 266 (2) ◽  
pp. 187-191 ◽  
Author(s):  
D.H. Canaday ◽  
C.J. Burant ◽  
L. Jones ◽  
H. Aung ◽  
L. Woc-Colburn ◽  
...  
Keyword(s):  
Antigen Processing ◽  
Hcv Infection ◽  
Mhc Ii ◽  
Chronic Hcv Infection ◽  
Chronic Hcv ◽  
Antigen Processing And Presentation

Research progress in predicting DNA methylation modifications and the relation with human diseases

2021 ◽  
Vol 28 ◽  
Author(s):  
Chunyan Ao ◽  
Lin Gao ◽  
Liang Yu
Keyword(s):  
Dna Methylation ◽  
Eukaryotic Cell ◽  
Machine Learning Algorithms ◽  
Research Progress ◽  
Epigenetic Mechanisms ◽  
Biological Processes ◽  
Prediction Tools ◽  
Transformation Mechanisms ◽  
The Relationship ◽  
Treatment And Diagnosis

: DNA methylation is an important mode of regulation in epigenetic mechanisms, and it is one of the research foci in the field of epigenetics. DNA methylation modification affects a series of biological processes, such as eukaryotic cell growth, differentiation and transformation mechanisms, by regulating gene expression. In this review, we systematically summarized the DNA methylation databases, prediction tools for DNA methylation modification, machine learning algorithms for predicting DNA methylation modification, and the relationship between DNA methylation modification and diseases such as hypertension, Alzheimer's disease, diabetic nephropathy, and cancer. An in-depth understanding of DNA methylation mechanisms can promote accurate prediction of DNA methylation modifications and the treatment and diagnosis of related diseases.

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