scholarly journals An in silico model of cytotoxic T-lymphocyte activation in the lymph node following short peptide vaccination

2018 ◽  
Vol 15 (140) ◽  
pp. 20180041 ◽  
Author(s):  
Liam V. Brown ◽  
Eamonn A. Gaffney ◽  
Jonathan Wagg ◽  
Mark C. Coles
Keyword(s):  
Lymph Node ◽  
In Silico ◽  
Cytotoxic T Lymphocyte ◽  
Lymphocyte Activation ◽  
Vaccination Strategy ◽  
Peptide Vaccination ◽  
Class I Mhc ◽  
Vaccination Site ◽  
Mhc I ◽  
Short Peptide

Tumour immunotherapy is dependent upon activation and expansion of tumour-targetting immune cells, known as cytotoxic T-lymphocytes (CTLs). Cancer vaccines developed in the past have had limited success and the mechanisms resulting in failure are not well characterized. To elucidate these mechanisms, we developed a human-parametrized, in silico , agent-based model of vaccination-driven CTL activation within a clinical short-peptide vaccination context. The simulations predict a sharp transition in the probability of CTL activation, which occurs with variation in the separation rate (or off-rate) of tumour-specific immune response-inducing peptides (cognate antigen) from the major histocompatibility class I (MHC-I) receptors of dendritic cells (DCs) originally at the vaccination site. For peptides with MHC-I off-rates beyond this transition, it is predicted that no vaccination strategy will lead to successful expansion of CTLs. For slower off-rates, below the transition, the probability of CTL activation becomes sensitive to the numbers of DCs and T cells that interact subsequent to DC migration to the draining lymph node of the vaccination site. Thus, the off-rate is a key determinant of vaccine design.

scholarly journals Tumor MHC Expression Guides First-Line Immunotherapy Selection in Melanoma

Cancers ◽  
2020 ◽  
Vol 12 (11) ◽  
pp. 3374
Author(s):  
Elena Shklovskaya ◽  
Jenny H Lee ◽  
Su Yin Lim ◽  
Ashleigh Stewart ◽  
Bernadette Pedersen ◽  
...  
Keyword(s):  
T Cell ◽  
Cytotoxic T Lymphocyte ◽  
Myeloid Cell ◽  
Combination Immunotherapy ◽  
First Line ◽  
Class I Mhc ◽  
Durable Response ◽  
Mhc I ◽  
Quantitative Score ◽  
Selection Of

Immunotherapy targeting T-cell inhibitory receptors, namely programmed cell death-1 (PD-1) and/or cytotoxic T-lymphocyte associated protein-4 (CTLA-4), leads to durable responses in a proportion of patients with advanced metastatic melanoma. Combination immunotherapy results in higher rates of response compared to anti-PD-1 monotherapy, at the expense of higher toxicity. Currently, there are no robust molecular biomarkers for the selection of first-line immunotherapy. We used flow cytometry to profile pretreatment tumor biopsies from 36 melanoma patients treated with anti-PD-1 or combination (anti-PD-1 plus anti-CTLA-4) immunotherapy. A novel quantitative score was developed to determine the tumor cell expression of antigen-presenting MHC class I (MHC-I) molecules, and to correlate expression data with treatment response. Melanoma MHC-I expression was intact in all tumors derived from patients who demonstrated durable response to anti-PD-1 monotherapy. In contrast, melanoma MHC-I expression was low in 67% of tumors derived from patients with durable response to combination immunotherapy. Compared to MHC-I high tumors, MHC-I low tumors displayed reduced T-cell infiltration and a myeloid cell-enriched microenvironment. Our data emphasize the importance of robust MHC-I expression for anti-PD-1 monotherapy response and provide a rationale for the selection of combination immunotherapy as the first-line treatment in MHC-I low melanoma.

scholarly journals Crystallization and preliminary X-ray diffraction analysis of the two distinct types of zebrafish β2-microglobulin

2015 ◽  
Vol 71 (6) ◽  
pp. 794-798 ◽  
Author(s):  
Zhaosan Chen ◽  
Nianzhi Zhang ◽  
Shuangshuang Lu ◽  
Mansoor Tariq ◽  
Junya Wang ◽  
...  
Keyword(s):  
Cytotoxic T Lymphocyte ◽  
Relevant Information ◽  
X Ray Diffraction ◽  
Unit Cell Parameters ◽  
Class I Mhc ◽  
Mhc I ◽  
X Ray ◽  
Cell Parameters ◽  
Histocompatibility Complex ◽  
Ctl Immune Response

β2-Microglobulin (β2m) noncovalently associates with the heavy chain of major histocompatibility complex class I (MHC I) molecules, which bind foreign antigen peptides to control the cytotoxic T lymphocyte (CTL) immune response. In contrast to mammals, there are distinct types of β2ms derived from two loci in a number of teleost species. In order to clarify the structures of the β2ms, the zebrafish (Danio rerio) β2msDare-β2m-I andDare-β2m-II were expressed inEscherichia coli, purified and crystallized, and diffraction data were collected to 1.6 and 1.9 Å resolution, respectively. Both crystals belonged to space groupP212121. The unit-cell parameters were determined to bea= 38.2,b= 50.4,c= 50.9 Å forDare-β2m-I anda= 38.9,b= 52.7,c= 65.8 Å forDare-β2m-II. Each asymmetric unit was constituted of one molecule, with Matthews coefficients of 2.22 and 3.01 Å3 Da−1and solvent contents of 45 and 59% forDare-β2m-I andDare-β2m-II, respectively. These two β2m structures will provide relevant information for further studies of the structures of the MHC I complex.

scholarly journals Integrative Analysis of HTNV Glycoprotein Derived MHC II Epitopes by In Silico Prediction and Experimental Validation

2021 ◽  
Vol 11 ◽  
Author(s):  
Hao Sun ◽  
Zhenhua Lu ◽  
Guoyun Xuan ◽  
Ning Liu ◽  
Tianhu Wang ◽  
...  
Keyword(s):  
In Silico ◽  
Rna Virus ◽  
Large Population ◽  
Hemorrhagic Fever ◽  
Hantaan Virus ◽  
Class I Mhc ◽  
Mhc I ◽  
Mhc Ii ◽  
Host Virus Interactions ◽  
Virus Interactions

Hantaan virus (HTNV), the causative pathogen of hemorrhagic fever with renal syndrome (HFRS), is a negative RNA virus belonging to the Orthohantaviridae family. HTNV envelope glycoprotein (GP), encoded by the genomic medium segment, is immunogenic and is therefore a promising vaccine candidate. Major histocompatibility complex class I (MHC-I) epitopes derived from HTNV has been extensively studied, but little is known of MHC-II epitopes. In silico predictions based on four databases indicated that the full-length HTNV GP has 1121 15-mer epitopes, of which 289 had a high score for binding to the human and murine MHC-II superfamily. It found that epitope ILTVLKFIANIFHTS could potentially bind most MHC-II molecules covering human and murine haplotypes. Dominant epitopes were validated by enzyme-linked immunospot assay of splenocytes from immunized mice; 6 of 10 epitopes supported the predictions including TATYSIVGPANAKVP, TKTLVIGQCIYTITS, FSLLPGVAHSIAVEL, CETYKELKAHGVSCP, CGLYLDRLKPVGSAY, and NLGENPCKIGLQTSS. Conservation analysis of dominant epitopes revealed host–virus interactions without geographic stratification, thus meeting the requirements of candidate vaccines for large-population prophylaxis. These findings provide insight into hantavirus antigenicity and suggest that vaccines targeting MHC-II could provide immune protection in large population to complement symptomatic therapies for the treatment of HFRS.

scholarly journals MHC class I antigen cross-presentation mediated by PapMV nanoparticles in human antigen-presenting cells is dependent on autophagy

PLoS ONE ◽  
2021 ◽  
Vol 16 (12) ◽  
pp. e0261987
Author(s):  
David Possamaï ◽  
Laïla-Aïcha Hanafi ◽  
Angélique Bellemare-Pelletier ◽  
Katia Hamelin ◽  
Paméla Thébault ◽  
...  
Keyword(s):  
Antigen Presentation ◽  
T Lymphocyte ◽  
Cytotoxic T Lymphocyte ◽  
Antigen Presenting Cells ◽  
Class I ◽  
Class I Mhc ◽  
Mhc I ◽  
Cross Presentation ◽  
Antigen Presenting ◽  
Papmv Nanoparticles

Nanoparticles made of the coat protein of papaya mosaic virus (PapMV) and a single-strand RNA were previously shown to be an efficient antigen presentation system for the trigger of cellular immunity. Engineering of PapMV nano with a cytotoxic T lymphocyte epitope was previously shown activating specific T lymphocytes through a proteasome-independent major histocompatibility complex class I (MHC-I) cross-presentation. In this study, we provide new insights into the mechanism of the MHC-I cross-presentation mediated by PapMV nanoparticles. We demonstrate that PapMV nanoparticles do not require the transporter associated with antigen presentation (TAP), but rather depend on lysosome acidification and cathepsin S protease activity for presentation of the T cell epitope. We have also linked the induction of autophagy with this vacuolar MHC-I cross-presentation process. Interestingly, autophagy is induced in antigen-presenting cells after PapMV nanoparticles exposure and inhibition of autophagy reduce MHC-I cross-presentation. This study demonstrates that autophagy is associated with TAP- and proteasome-independent MHC-I cross-presentation. A deeper understanding of the autophagy-dependent MHC-I cross-presentation will be useful in designing vaccination platforms that aim to trigger an efficient cytotoxic T lymphocyte response.

scholarly journals CD8+Cytotoxic-T-Lymphocyte Breadth Could Facilitate Early Immune Detection of Immunodeficiency Virus-Derived Epitopes with Limited Expression Levels

mSphere ◽  
2019 ◽  
Vol 4 (1) ◽  
Author(s):  
Tetsuo Tsukamoto ◽  
Hiroyuki Yamamoto ◽  
Tetsuro Matano
Keyword(s):  
T Lymphocyte ◽  
Cytotoxic T Lymphocyte ◽  
Physical Contact ◽  
Class I Mhc ◽  
Mhc I ◽  
Expression Levels ◽  
Immunodeficiency Virus ◽  
Infected Cells ◽  
Attenuated Viruses

ABSTRACTCytotoxic-T-lymphocyte (CTL) responses are important to control the replication of human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV). Accumulating evidence suggests that the ability of a few immunodominant T-cell populations to detect and kill HIV/SIV-infected cells is important in individuals with a protective major histocompatibility complex class I (MHC-I) allele. On the other hand, immunization with live(-attenuated) viruses may be effective against superinfection of virulent viral strains regardless of the host’s MHC-I haplotypes, although the underlying mechanisms have not been fully documented. In this article, we propose a hypothesis that the early detection of infected cells in superinfected individuals may be partly facilitated by recognition of diverse CTL epitopes with limited expression levels. We further explain the hypothesis using simple mathematics that was written based on previousin vitroviral suppression assay results and by considering the physical contact of infected cells with CTLs.

scholarly journals Immunoinformatic approach to assess SARS-CoV-2 protein S epitopes recognised by the most frequent MHC-I alleles in the Brazilian population

2020 ◽  
pp. jclinpath-2020-206946 ◽  
Author(s):  
Ronald Rodrigues de Moura ◽  
Almerinda Agrelli ◽  
Carlos André Santos-Silva ◽  
Natália Silva ◽  
Bruno Rodrigo Assunção ◽  
...  
Keyword(s):  
Immune Response ◽  
In Silico ◽  
Human Leukocyte ◽  
In Silico Analysis ◽  
Protein S ◽  
Data Bank ◽  
Brazilian Population ◽  
Class I Mhc ◽  
Mhc I ◽  
Genetic Isolates

AimsBrazil is nowadays one of the epicentres of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic and new therapies are needed to face it. In the context of specific immune response against the virus, a correlation between Major Histocompatibility Complex Class I (MHC-I) and the severity of the disease in patients with COVID-19 has been suggested. Aiming at better understanding the biology of the infection and the immune response against the virus in the Brazilian population, we analysed SARS-CoV-2 protein S peptides in order to identify epitopes able to elicit an immune response mediated by the most frequent MHC-I alleles using in silico methods.MethodsOur analyses consisted in searching for the most frequent Human Leukocyte Antigen (HLA)-A, HLA-B and HLA-C alleles in the Brazilian population, excluding the genetic isolates; then, we performed: molecular modelling for unsolved structures, MHC-I binding affinity and antigenicity prediction, peptide docking and molecular dynamics of the best fitted MHC-I/protein S complexes.ResultsWe identified 24 immunogenic epitopes in the SARS-CoV-2 protein S that could interact with 17 different MHC-I alleles (namely, HLA-A*01:01; HLA-A*02:01; HLA-A*11:01; HLA-A*24:02; HLA-A*68:01; HLA-A*23:01; HLA-A*26:01; HLA-A*30:02; HLA-A*31:01; HLA-B*07:02; HLA-B*51:01; HLA-B*35:01; HLA-B*44:02; HLA-B*35:03; HLA-C*05:01; HLA-C*07:01 and HLA-C*15:02) in the Brazilian population.ConclusionsBeing aware of the intrinsic limitations of in silico analysis (mainly the differences between the real and the Protein Data Bank (PDB) structure; and accuracy of the methods for simulate proteasome cleavage), we identified 24 epitopes able to interact with 17 MHC-I more frequent alleles in the Brazilian population that could be useful for the development of strategic methods for vaccines against SARS-CoV-2.

scholarly journals gp96-Peptide Vaccination of Mice against Intracellular Bacteria

2001 ◽  
Vol 69 (6) ◽  
pp. 4164-4167 ◽  
Author(s):  
Ulrich Zügel ◽  
Anne-Marit Sponaas ◽  
Jutta Neckermann ◽  
Bernd Schoel ◽  
Stefan H. E. Kaufmann
Keyword(s):  
T Lymphocyte ◽  
Cytotoxic T Lymphocyte ◽  
Bacterial Pathogens ◽  
Vaccination Strategy ◽  
Intracellular Bacteria ◽  
Peptide Vaccination ◽  
Lymphocyte Responses

ABSTRACT This work demonstrates that gp96 preparations isolated from cells infected with intracellular bacteria induce cytotoxic T-lymphocyte responses and confer protection. Our findings extend previous reports on the immunogenicity of gp96-associated peptides to antigens derived from intracellular bacteria. Immunization with gp96 may therefore represent a promising vaccination strategy against bacterial pathogens.

Ligand Design for Specific MHC Class I Molecules on the Cell Surface

2020 ◽  
Author(s):  
Xizheng Sun ◽  
Reika Tokunaga ◽  
Yoko Nagai ◽  
Ryo Miyahara ◽  
Akihiro Kishimura ◽  
...  
Keyword(s):  
Cell Surface ◽  
Mhc Class I ◽  
Targeted Delivery ◽  
Peptide Ligands ◽  
Class I ◽  
Class I Mhc ◽  
Mhc I ◽  
Histocompatibility Complex ◽  
High Binding Affinity ◽  
Mhc Class I Molecules

<p><a></a><a></a><a>We have validated that ligand peptides designed from antigen peptides could be used for targeting specific major histocompatibility complex class I (MHC-I)</a> molecules on cell surface. To design the ligand peptides, we used reported antigen peptides for each MHC-I molecule with high binding affinity. From the crystal structure of the peptide/MHC-I complexes, we determined a modifiable residue in the antigen peptides and replaced this residue with a lysine with an ε-amine group modified with functional molecules. The designed ligand peptides successfully bound to cells expressing the corresponding MHC-I molecules via exchange of peptides bound to the MHC-I. We demonstrated that the peptide ligands could be used to transport a protein or a liposome to cells expressing the corresponding MHC-I. The present strategy may be useful for targeted delivery to cells overexpressing MHC-I, which have been observed autoimmune diseases.</p>

scholarly journals Immune Checkpoints, Inhibitors and Radionuclides in Prostate Cancer: Promising Combinatorial Therapy Approach

2021 ◽  
Vol 22 (8) ◽  
pp. 4109
Author(s):  
Mankgopo M. Kgatle ◽  
Tebatso M. G. Boshomane ◽  
Ismaheel O. Lawal ◽  
Kgomotso M. G. Mokoala ◽  
Neo P. Mokgoro ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Cytotoxic T Lymphocyte ◽  
Cancer Control ◽  
Lymphocyte Activation ◽  
Immune Checkpoints ◽  
Mortality And Morbidity ◽  
Domain 3

Emerging research demonstrates that co-inhibitory immune checkpoints (ICs) remain the most promising immunotherapy targets in various malignancies. Nonetheless, ICIs have offered insignificant clinical benefits in the treatment of advanced prostate cancer (PCa) especially when they are used as monotherapies. Current existing PCa treatment initially offers an improved clinical outcome and overall survival (OS), however, after a while the treatment becomes resistant leading to aggressive and uncontrolled disease associated with increased mortality and morbidity. Concurrent combination of the ICIs with radionuclides therapy that has rapidly emerged as safe and effective targeted approach for treating PCa patients may shift the paradigm of PCa treatment. Here, we provide an overview of the contextual contribution of old and new emerging inhibitory ICs in PCa, preclinical and clinical studies supporting the use of these ICs in treating PCa patients. Furthermore, we will also describe the potential of using a combinatory approach of ICIs and radionuclides therapy in treating PCa patients to enhance efficacy, durable cancer control and OS. The inhibitory ICs considered in this review are cytotoxic T-lymphocyte antigen 4 (CTLA4), programmed cell death 1 (PD1), V-domain immunoglobulin suppressor of T cell activation (VISTA), indoleamine 2,3-dioxygenase (IDO), T cell Immunoglobulin Domain and Mucin Domain 3 (TIM-3), lymphocyte-activation gene 3 (LAG-3), T cell immunoreceptor with Ig and ITIM domains (TIGIT), B7 homolog 3 (B7-H3) and B7-H4.

scholarly journals Soluble and Exosome-Bound α-Galactosylceramide Mediate Preferential Proliferation of Educated NK Cells with Increased Anti-Tumor Capacity

Cancers ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 298
Author(s):  
Arnika K. Wagner ◽  
Ulf Gehrmann ◽  
Stefanie Hiltbrunner ◽  
Valentina Carannante ◽  
Thuy T. Luu ◽  
...  
Keyword(s):  
Nk Cells ◽  
Cancer Immunotherapy ◽  
Nk Cell ◽  
Mouse Strains ◽  
Target Cells ◽  
Class I Mhc ◽  
Mhc I ◽  
Cell Responses ◽  
Missing Self

Natural killer (NK) cells can kill target cells via the recognition of stress molecules and down-regulation of major histocompatibility complex class I (MHC-I). Some NK cells are educated to recognize and kill cells that have lost their MHC-I expression, e.g., tumor or virus-infected cells. A desired property of cancer immunotherapy is, therefore, to activate educated NK cells during anti-tumor responses in vivo. We here analyze NK cell responses to α-galactosylceramide (αGC), a potent activator of invariant NKT (iNKT) cells, or to exosomes loaded with αGC. In mouse strains which express different MHC-I alleles using an extended NK cell flow cytometry panel, we show that αGC induces a biased NK cell proliferation of educated NK cells. Importantly, iNKT cell-induced activation of NK cells selectively increased in vivo missing self-responses, leading to more effective rejection of tumor cells. Exosomes from antigen-presenting cells are attractive anti-cancer therapy tools as they may induce both innate and adaptive immune responses, thereby addressing the hurdle of tumor heterogeneity. Adding αGC to antigen-loaded dendritic-cell-derived exosomes also led to an increase in missing self-responses in addition to boosted T and B cell responses. This study manifests αGC as an attractive adjuvant in cancer immunotherapy, as it increases the functional capacity of educated NK cells and enhances the innate, missing self-based antitumor response.

Sign in / Sign up

Export Citation Format

Share Document