scholarly journals TCR contact residue hydrophobicity is a hallmark of immunogenic CD8+ T cell epitopes

2015 ◽  
Vol 112 (14) ◽  
pp. E1754-E1762 ◽  
Author(s):  
Diego Chowell ◽  
Sri Krishna ◽  
Pablo D. Becker ◽  
Clément Cocita ◽  
Jack Shu ◽  
...  
Keyword(s):  
T Cell ◽  
Tumor Antigens ◽  
Vaccine Development ◽  
Cell Receptor ◽  
Biochemical Properties ◽  
Immune Recognition ◽  
T Cell Epitopes ◽  
Gag Protein ◽  
Contact Residues

Despite the availability of major histocompatibility complex (MHC)-binding peptide prediction algorithms, the development of T-cell vaccines against pathogen and tumor antigens remains challenged by inefficient identification of immunogenic epitopes. CD8+ T cells must distinguish immunogenic epitopes from nonimmunogenic self peptides to respond effectively against an antigen without endangering the viability of the host. Because this discrimination is fundamental to our understanding of immune recognition and critical for rational vaccine design, we interrogated the biochemical properties of 9,888 MHC class I peptides. We identified a strong bias toward hydrophobic amino acids at T-cell receptor contact residues within immunogenic epitopes of MHC allomorphs, which permitted us to develop and train a hydrophobicity-based artificial neural network (ANN-Hydro) to predict immunogenic epitopes. The immunogenicity model was validated in a blinded in vivo overlapping epitope discovery study of 364 peptides from three HIV-1 Gag protein variants. Applying the ANN-Hydro model on existing peptide-MHC algorithms consistently reduced the number of candidate peptides across multiple antigens and may provide a correlate with immunodominance. Hydrophobicity of TCR contact residues is a hallmark of immunogenic epitopes and marks a step toward eliminating the need for empirical epitope testing for vaccine development.

scholarly journals Oral Vaccination with Attenuated Salmonella enterica Strains Encoding T-Cell Epitopes from Tumor Antigen NY-ESO-1 Induces Specific Cytotoxic T-Lymphocyte Responses

2010 ◽  
Vol 17 (6) ◽  
pp. 889-894 ◽  
Author(s):  
Jia-Zi Meng ◽  
Yu-Jun Dong ◽  
He Huang ◽  
Shuang Li ◽  
Yi Zhong ◽  
...  
Keyword(s):  
T Cell ◽  
T Lymphocyte ◽  
Salmonella Enterica ◽  
Cytotoxic T Lymphocyte ◽  
T Cell Response ◽  
Target Antigen ◽  
Immune Recognition ◽  
T Cell Epitopes ◽  
Replacement Method

ABSTRACT Bacterial fimbriae can accept foreign peptides and display them on the cell surface. A highly efficient gene replacement method was used to generate peptide vaccines based on Salmonella enterica serovar Typhimurium SL3261. The T-cell epitopes (NY-ESO-1 p157-165 and p157-167) from NY-ESO-1, which is a promising target antigen in patients for the specific immune recognition of cancer, were incorporated into the gene encoding AgfA (the major subunit protein of thin aggregative fimbriae of Salmonella) by replacing an equal length of the DNA segment. To improve cytotoxic T-lymphocyte recognition, both termini of the peptide were flanked by double alanine (AA) residues. Immunofluorescence microscopy with AgfA-specific antiserum verified the expression of chimeric AgfA, which was also proved by a Congo red binding assay. Oral immunizations of HLA-A*0201 transgenic mice with recombinant SL3261 strains encoding NY-ESO-1 p157-165 or p157-167 induced NY-ESO-1 p157-165-specific CD8+ T cells, detected by an HLA-A*0201 pentamer, and induced a T-cell response detected by an enzyme-linked immunospot assay. The Salmonella fimbrial display system was efficient at the induction of an antitumor cellular immune response in vivo, providing a new strategy for the development of efficient cancer vaccinations.

scholarly journals Comprehensive mutagenesis identifies the peptide repertoire of a p53 T-cell receptor mimic antibody that displays no toxicity in mice transgenic for human HLA-A*0201

PLoS ONE ◽  
2021 ◽  
Vol 16 (4) ◽  
pp. e0249967
Author(s):  
Iva Trenevska ◽  
Amanda P. Anderson ◽  
Carol Bentley ◽  
Tasneem Hassanali ◽  
Sarah Wiblin ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Receptor ◽  
Tumor Antigens ◽  
Mutational Analysis ◽  
Cell Receptor ◽  
Class I Mhc ◽  
Mhc I ◽  
Peptide Specificity ◽  
Histocompatibility Complex

T-cell receptor mimic (TCRm) antibodies have expanded the repertoire of antigens targetable by monoclonal antibodies, to include peptides derived from intracellular proteins that are presented by major histocompatibility complex class I (MHC-I) molecules on the cell surface. We have previously used this approach to target p53, which represents a valuable target for cancer immunotherapy because of the high frequency of its deregulation by mutation or other mechanisms. The T1-116C TCRm antibody targets the wild type p5365-73 peptide (RMPEAAPPV) presented by HLA-A*0201 (HLA-A2) and exhibited in vivo efficacy against triple receptor negative breast cancer xenografts. Here we report a comprehensive mutational analysis of the p53 RMPEAAPPV peptide to assess the T1-116C epitope and its peptide specificity. Antibody binding absolutely required the N-terminal arginine residue, while amino acids in the center of the peptide contributed little to specificity. Data mining the immune epitope database with the T1-116C binding consensus and validation of peptide recognition using the T2 stabilization assay identified additional tumor antigens targeted by T1-116C, including WT1, gp100, Tyrosinase and NY-ESO-1. Most peptides recognized by T1-116C were conserved in mice and human HLA-A2 transgenic mice showed no toxicity when treated with T1-116C in vivo. We conclude that comprehensive validation of TCRm antibody target specificity is critical for assessing their safety profile.

TCR signal strength defines distinct mechanisms of T cell dysfunction and cancer evasion

2021 ◽  
Vol 219 (2) ◽  
Author(s):  
Mojdeh Shakiba ◽  
Paul Zumbo ◽  
Gabriel Espinosa-Carrasco ◽  
Laura Menocal ◽  
Friederike Dündar ◽  
...  
Keyword(s):  
T Cell ◽  
Tumor Antigens ◽  
Cell Function ◽  
Signal Strength ◽  
Cell Receptor ◽  
Fine Tuning ◽  
Tumor Control ◽  
High Signal ◽  
Tumor Escape

T cell receptor (TCR) signal strength is a key determinant of T cell responses. We developed a cancer mouse model in which tumor-specific CD8 T cells (TST cells) encounter tumor antigens with varying TCR signal strength. High-signal-strength interactions caused TST cells to up-regulate inhibitory receptors (IRs), lose effector function, and establish a dysfunction-associated molecular program. TST cells undergoing low-signal-strength interactions also up-regulated IRs, including PD1, but retained a cell-intrinsic functional state. Surprisingly, neither high- nor low-signal-strength interactions led to tumor control in vivo, revealing two distinct mechanisms by which PD1hi TST cells permit tumor escape; high signal strength drives dysfunction, while low signal strength results in functional inertness, where the signal strength is too low to mediate effective cancer cell killing by functional TST cells. CRISPR-Cas9–mediated fine-tuning of signal strength to an intermediate range improved anti-tumor activity in vivo. Our study defines the role of TCR signal strength in TST cell function, with important implications for T cell–based cancer immunotherapies.

scholarly journals Discordant Brucella melitensis Antigens Yield Cognate CD8+ T Cells In Vivo

2009 ◽  
Vol 78 (1) ◽  
pp. 168-176 ◽  
Author(s):  
Marina A. Durward ◽  
Jerome Harms ◽  
Diogo M. Magnani ◽  
Linda Eskra ◽  
Gary A. Splitter
Keyword(s):  
T Cells ◽  
T Cell ◽  
Vaccine Development ◽  
Brucella Melitensis ◽  
T Cell Response ◽  
T Cell Epitopes ◽  
Macrophage Infection ◽  
Genes Encoding ◽  
Human Vaccine

ABSTRACT Brucella spp. are intracellular bacteria that cause the most frequent zoonosis in the world. Although recent work has advanced the field of Brucella vaccine development, there remains no safe human vaccine. In order to produce a safe and effective human vaccine, the immune response to Brucella spp. requires greater understanding. Induction of Brucella-specific CD8+ T cells is considered an important aspect of the host response; however, the CD8+ T-cell response is not clearly defined. Discovering the epitope containing antigens recognized by Brucella-specific CD8+ T cells and correlating them with microarray data will aid in determining proteins critical for vaccine development that cover a kinetic continuum during infection. Developing tools to take advantage of the BALB/c mouse model of Brucella melitensis infection will help to clarify the correlates of immunity and improve the efficacy of this model. Two H-2d CD8+ T-cell epitopes have been characterized, and a group of immunogenic proteins have provoked gamma interferon production by CD8+ T cells. RYCINSASL and NGSSSMATV induced cognate CD8+ T cells after peptide immunization that showed specific killing in vivo. Importantly, we found by microarray analysis that the genes encoding these epitopes are differentially expressed following macrophage infection, further emphasizing that these discordant genes may play an important role in the pathogenesis of B. melitensis infection.

scholarly journals T Cell Epitope Screening of Epstein-Barr Virus Fusion Protein gB

2021 ◽  
Vol 95 (10) ◽  
Author(s):  
Haiwen Chen ◽  
Xiao Zhang ◽  
Shanshan Zhang ◽  
Xiaobing Duan ◽  
Tong Xiang ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Vaccine Development ◽  
T Cell Responses ◽  
Target Antigen ◽  
T Cell Epitopes ◽  
Cell Responses ◽  
Ebv Infection ◽  
Ebv Reactivation

ABSTRACT Glycoprotein B (gB) is an essential fusion protein for Epstein-Barr virus (EBV) infection of both B cells and epithelial cells and is thus a promising target antigen for a prophylactic vaccine to prevent or reduce EBV-associated disease. T cell responses play key roles in the control of persistent EBV infection and the efficacy of a vaccine. However, to date, T cell responses to gB have been characterized for only a limited number of human leukocyte antigen (HLA) alleles. Here, we screened gB T cell epitopes in 23 healthy EBV carriers and 10 patients with nasopharyngeal cancer (NPC) using a peptide library spanning the entire gB sequence. We identified 12 novel epitopes in the context of seven new HLA restrictions that are common in Asian populations. Two epitopes, gB214–223 and gB840–849, restricted by HLA-B*58:01 and -B*38:02, respectively, elicited specific CD8+ T cell responses to inhibit EBV-driven B cell transformation. Interestingly, gB-specific CD8+ T cells were more frequent in healthy viral carriers with EBV reactivation than in those without EBV reactivation, indicating that EBV reactivation in vivo stimulates both humoral (VCA-gp125-IgA) and cellular responses to gB. We further found that most gB epitopes are conserved among different EBV strains. Our study broadens the diversity and HLA restrictions of gB epitopes and suggests that gB is a common target of T cell responses in healthy viral carriers with EBV reactivation. In particular, the precisely mapped and conserved gB epitopes provide valuable information for prophylactic vaccine development. IMPORTANCE T cells are crucial for the control of persistent EBV infection and the development of EBV-associated diseases. The EBV gB protein is essential for virus entry into B cells and epithelial cells and is thus a target antigen for vaccine development. Understanding T cell responses to gB is important for subunit vaccine design. Here, we comprehensively characterized T cell responses to full-length gB. Our results expand the available gB epitopes and HLA restrictions, particularly those common in Asian populations. Furthermore, we showed that gB-specific CD8+ T cells inhibit B cell transformation ex vivo and that gB-specific CD8+ T cell responses in vivo may be associated with intermittent EBV reactivation in asymptomatic viral carriers. These gB epitopes are highly conserved among geographically separated EBV strains. Precisely mapped and conserved T cell epitopes may contribute to immune monitoring and the development of a gB subunit vaccine.

scholarly journals Design of T cell epitope-based vaccine candidate for SARS-CoV-2 targeting nucleocapsid and spike protein escape variants

2021 ◽  
Author(s):  
Gabriel Jabbour ◽  
Samantha Rego ◽  
Vincent Nguyenkhoa ◽  
Sivanesan Dakshanamurthy
Keyword(s):  
T Cell ◽  
Vaccine Development ◽  
Cell Epitope ◽  
Epitope Prediction ◽  
T Cell Epitopes ◽  
Clinical Predictors ◽  
Nucleocapsid Proteins ◽  
Global Concern

AbstractThe current COVID-19 pandemic continues to spread and devastate in the absence of effective treatments, warranting global concern and action. Despite progress in vaccine development, the rise of novel, increasingly infectious SARS-CoV-2 variants makes it clear that our response to the virus must continue to evolve along with it. The use of immunoinformatics provides an opportunity to rapidly and efficiently expand the tools at our disposal to combat the current pandemic and prepare for future outbreaks through epitope-based vaccine design. In this study, we validated and compared the currently available epitope prediction tools, and then used the best tools to predict T cell epitopes from SARS-CoV-2 spike and nucleocapsid proteins for use in an epitope-based vaccine. We combined the mouse MHC affinity predictor and clinical predictors such as HLA affinity, immunogenicity, antigenicity, allergenicity, toxicity and stability to select the highest quality CD8 and CD4 T cell epitopes for the common SARS-CoV-2 variants of concern suitable for further preclinical studies. We also identified variant-specific epitopes to more precisely target the Alpha, Beta, Gamma, Delta, Cluster 5 and US variants. We then modeled the 3D structures of our top 4 N and S epitopes to investigate the molecular interaction between peptide-MHC and peptide-MHC-TCR complexes. Following in vitro and in vivo validation, the epitopes identified by this study may be used in an epitope-based vaccine to protect across all current variants, as well as in variant-specific booster shots to target variants of concern. Immunoinformatics tools allowed us to efficiently predict epitopes in silico most likely to prove effective in vivo, providing a more streamlined process for vaccine development in the context of a rapidly evolving pandemic.

Use of T Cell Epitopes for Vaccine Development

2001 ◽  
Vol 1 (3) ◽  
pp. 303-313 ◽  
Author(s):  
H. Sbai ◽  
A. Mehta ◽  
A. DeGroot
Keyword(s):  
T Cell ◽  
Vaccine Development ◽  
T Cell Epitopes

scholarly journals Fusion transcripts FYN-TRAF3IP2 and KHDRBS1-LCK hijack T cell receptor signaling in peripheral T-cell lymphoma, not otherwise specified

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Koen Debackere ◽  
Lukas Marcelis ◽  
Sofie Demeyer ◽  
Marlies Vanden Bempt ◽  
Nicole Mentens ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Receptor ◽  
Cell Lymphoma ◽  
Ex Vivo ◽  
Cell Receptor ◽  
T Cell Lymphoma ◽  
Peripheral T Cell Lymphoma ◽  
Fusion Transcripts ◽  
Not Otherwise Specified

AbstractPeripheral T-cell lymphoma (PTCL) is a heterogeneous group of non-Hodgkin lymphomas with poor prognosis. Up to 30% of PTCL lack distinctive features and are classified as PTCL, not otherwise specified (PTCL-NOS). To further improve our understanding of the genetic landscape and biology of PTCL-NOS, we perform RNA-sequencing of 18 cases and validate results in an independent cohort of 37 PTCL cases. We identify FYN-TRAF3IP2, KHDRBS1-LCK and SIN3A-FOXO1 as new in-frame fusion transcripts, with FYN-TRAF3IP2 as a recurrent fusion detected in 8 of 55 cases. Using ex vivo and in vivo experiments, we demonstrate that FYN-TRAF3IP2 and KHDRBS1-LCK activate signaling pathways downstream of the T cell receptor (TCR) complex and confer therapeutic vulnerability to clinically available drugs.

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