scholarly journals The landscape of T cell epitope immunogenicity in sequence space

2017 ◽  
Author(s):  
Masato Ogishi ◽  
Hiroshi Yotsuyanagi
Keyword(s):  
T Cell ◽  
Cell Epitope ◽  
Cell Receptor ◽  
Single Amino Acid ◽  
Cell Reactivity ◽  
Human T Cell ◽  
Cell Immunity ◽  
Tcr Repertoire ◽  
Individualized Approach ◽  
T Cell Reactivity

SummaryThe existence of population-wide T cell immunity is widely recognized for multiple pathogen-derived immunodominant epitopes, despite the vast diversity and individualized nature of T cell receptor (TCR) repertoire. We thus hypothesized that population-wide epitope immunogenicity could be probabilistically defined by exploiting public TCR features. To gain a proof-of-concept, here we describe a machine learning framework yielding probabilistic estimates of immunogenicity, termed “immunogenicity scores”, by utilizing features designed to mimic thermodynamic interactions between peptides bound to major histocompatibility complex (MHC) and TCR repertoire. Immunogenicity score dynamics among observed and computationally simulated single amino acid mutants delineated the landscape of position- and residue-specific mutational impacts, and even quantitatively estimated escaping potentials of known epitopes with remarkable positional specificity. This study illustrates that the population-wide aspect of adaptive immunity is predictable via non-individualized approach, possibly indicating antigen-guided convergence of human T cell reactivity.

scholarly journals Probing T-cell response by sequence-based probabilistic modeling

2020 ◽  
Author(s):  
Barbara Bravi ◽  
Vinod P. Balachandran ◽  
Benjamin D. Greenbaum ◽  
Aleksandra M. Walczak ◽  
Thierry Mora ◽  
...  
Keyword(s):  
T Cell ◽  
Probabilistic Models ◽  
Cell Receptor ◽  
T Cell Response ◽  
Specific Response ◽  
Sequence Motifs ◽  
Antigen Specificity ◽  
Human T Cell ◽  
Machine Learning Approach ◽  
Tcr Repertoire

AbstractWith the increasing ability to use high-throughput next-generation sequencing to quantify the diversity of the human T cell receptor (TCR) repertoire, the ability to use TCR sequences to infer antigen-specificity could greatly aid potential diagnostics and therapeutics. Here, we use a machine-learning approach known as Restricted Boltzmann Machine to develop a sequence-based inference approach to identify antigen-specific TCRs. Our approach combines probabilistic models of TCR sequences with clone abundance information to extract TCR sequence motifs central to an antigen-specific response. We use this model to identify patient personalized TCR motifs that respond to individual tumor and infectious disease antigens, and to accurately discriminate specific from non-specific responses. Furthermore, the hidden structure of the model results in an interpretable representation space where TCRs responding to the same antigen cluster, correctly discriminating the response of TCR to different viral epitopes. The model can therefore be used to identify both experimental and condition specific responding TCRs, of great importance to advancing personalized immunotherapies.

scholarly journals Evaluation of T Cell Immunity against Human Cytomegalovirus: Impact on Patient Management and Risk Assessment of Vertical Transmission

2016 ◽  
Vol 2016 ◽  
pp. 1-8 ◽  
Author(s):  
Giulia Freer ◽  
Paola Quaranta ◽  
Mauro Pistello
Keyword(s):  
T Cell ◽  
Solid Organ Transplantation ◽  
Solid Organ ◽  
Infectious Agents ◽  
Cmv Infection ◽  
Active Infection ◽  
Cell Reactivity ◽  
Cell Immunity ◽  
Pros And Cons ◽  
T Cell Reactivity

Cytomegalovirus (CMV) is one of the most common infectious agents, infecting the general population at an early age without causing morbidity most of the time. However, on particular occasions, it may represent a serious risk, as active infection is associated with rejection and disease after solid organ transplantation or fetal transmission during pregnancy. Several methods for CMV diagnosis are available on the market, but because infection is so common, careful selection is needed to discriminate primary infection from reactivation. This review focuses on methods based on CMV-specific T cell reactivity to help monitor the consequences of CMV infection/reactivation in specific categories of patients. This review makes an attempt at discussing the pros and cons of the methods available.

scholarly journals Impact of pre-existing T cell immunity to SARS-CoV-2 in uninfected individuals with COVID-19 mortality in different countries

2020 ◽  
Author(s):  
Gennadi V. Glinsky
Keyword(s):  
T Cells ◽  
T Cell ◽  
Herd Immunity ◽  
Inverse Correlation ◽  
Mortality Rates ◽  
Virus Spread ◽  
Cell Reactivity ◽  
Cell Immunity ◽  
Potential Impact ◽  
T Cell Reactivity

AbstractSeveral recent studies identified SARS-CoV-2 reactive T cells in people without exposure to the virus. However, pathophysiological implications of these findings remain unknown. Here, the potential impact of pre-existing T cell reactivity against SARS-CoV-2 in uninfected individuals on markedly different COVID-19 mortality levels in different countries has been investigated. The inverse correlation is documented between the prevalence of pre-existing SARS-CoV-2 reactive T cells in people without exposure to the virus and COVID-19 mortality rates in different countries. In countries with similar levels of pre-existing SARS-CoV-2 cross-reactive T cells in uninfected individuals, differences in COVID-19 mortality appear linked with the extend and consistency of implementations of social measures designed to limit the transmission of SARS-CoV-2 (lockdown; physical distancing; mask wearing). Collectively, these observations support the model that the level of pre-existing SARS-CoV-2 reactive T cells is one of the important determinants of the innate herd immunity against COVID-19. Together with the consistent social measures directed to limit the virus spread, high levels of pre-existing SARS-CoV-2 reactive T cells appear significant determinants diminishing the COVID-19 mortality. Observations reported in this contribution should have significant impact on definitions of the herd immunity threshold required to effectively stop the pandemic in different countries across the globe.

Interrogating CD8+ T cell reactivity on a genome-wide scale

2019 ◽  
Vol 11 (506) ◽  
pp. eaaz0302
Author(s):  
Kamila Naxerova
Keyword(s):  
T Cell ◽  
Large Scale ◽  
Cd8 T Cell ◽  
Cell Reactivity ◽  
Human T Cell ◽  
Genome Wide ◽  
A Genome ◽  
T Cell Antigens ◽  
Wide Scale ◽  
T Cell Reactivity

A new method enables large-scale identification of human T cell antigens.

scholarly journals Modulation of promiscuous T cell receptor recognition by mutagenesis of CDR2 residues.

1996 ◽  
Vol 183 (5) ◽  
pp. 2043-2051 ◽  
Author(s):  
J V Brawley ◽  
P Concannon
Keyword(s):  
T Cell ◽  
T Cell Receptor ◽  
Cell Receptor ◽  
Jurkat Cells ◽  
Single Amino Acid ◽  
Peptide Antigen ◽  
T Cell Clones ◽  
Human T Cell ◽  
Cdr3 Region ◽  
Cell Clones

The T cell receptor (TCR) recognizes a ligand composed of a major histocompatibility complex (MHC) molecule and a peptide antigen. Prior studies of murine T cell clones have demonstrated that residues in the CDR3 region of TCR interact with amino acids in the peptide during MHC-restricted antigen recognition. However, the questions of whether direct TCR MHC contacts are made and where such contact sites might map in the TCR have not been resolved. In this study, we have taken advantage of the promiscuous recognition of a peptide from influenza virus (HA 307-319) by human T cell clones to map sites in the TCR that mediate differences in human leukocyte antigen-D related (HLA-DR) restriction in the presence of a common peptide antigen. Site-specific mutagenesis of cloned TCR genes and transfection into Jurkat cells were used to demonstrate that single amino acid substitutions in CDR2 of the TCR-alpha chain controlled whether a T cell was restricted by the product of a single DR allele (DR7) or would respond to the HA 307-319 peptide when presented by the products of one of several different DR alleles (DR1, DR4, DR5, or DR7). Because the relevant DR alleles are defined by polymorphism in the DR-beta chain, these results also suggest a rotational orientation for recognition in which TCR-alpha interacts with DR beta.

scholarly journals Preserved T cell reactivity to the SARS-CoV-2 Omicron variant indicates continued protection in vaccinated individuals.

2021 ◽  
Author(s):  
Lorenzo De Marco ◽  
Silvia D'Orso ◽  
Marta Pirronello ◽  
Alice Verdiani ◽  
Andrea Termine ◽  
...  
Keyword(s):  
T Cell ◽  
Severe Disease ◽  
Spike Protein ◽  
Immune Recognition ◽  
Immune Protection ◽  
Cell Reactivity ◽  
Cell Responses ◽  
Cell Immunity ◽  
T Cell Reactivity ◽  
Study Setting

Importance: The emergence of the highly contagious Omicron variant of SARS-CoV-2 and the findings of a significantly reduced neutralizing potency of sera from convalescent or vaccinated individuals imposes the study of cellular immunity to predict the degree of immune protection to the yet again new coronavirus. Design: Prospective monocentric observational study. Setting: Conducted between December 20-21 at the Santa Lucia Foundation IRCCS. Participants: 61 volunteers (Mean age 41.62, range 21-62; 38F/23M) with different vaccination and SARS-CoV-2 infection backgrounds donated 15 ml of blood. Of these donors, one had recently completed chemotherapy, and one was undergoing treatment with monoclonal antibodies; the others reported no known health issue. Main Outcome(s) and Measure(s): The outcomes were the measurement of T cell reactivity to the mutated regions of the Spike protein of the Omicron SARS-CoV-2 variant and the assessment of remaining T cell immunity to the spike protein by stimulation with peptide libraries. Results: Lymphocytes from freshly drawn blood samples were isolated and immediately tested for reactivity to the Spike protein of SARS-CoV-2. T cell responses to peptides covering the mutated regions in the Omicron variant were decreased by over 47% compared to the same regions of the ancestral vaccine strain. However, overall reactivity to the peptide library of the full-length protein was largely maintained (estimated 83%). No significant differences in loss of immune recognition were identified between groups of donors with different vaccination and/or infection histories. Conclusions and Relevance: We conclude that despite the mutations in the Spike protein, the SARS-CoV-2 Omicron variant is nonetheless recognized by the cellular component of the immune system. It is reasonable to assume that protection from hospitalization and severe disease is maintained.

scholarly journals T Cell Reactivity to Regulatory Factor X4 in Type 1 Narcolepsy

2021 ◽  
Author(s):  
Guo Luo ◽  
Selina Yogeshwar ◽  
Ling Lin ◽  
Emmanuel Mignot
Keyword(s):  
T Cell ◽  
Human Leukocyte ◽  
Autoimmune Disorder ◽  
Cell Receptor ◽  
Cd4 T Cell ◽  
Regulatory Factor ◽  
Cell Reactivity ◽  
2009 H1n1 ◽  
T Cell Reactivity

Abstract Type 1 narcolepsy is strongly (98%) associated with human leukocyte antigen (HLA) class II DQA1*01:02/DQB1*06:02 (DQ0602) and highly associated with T cell receptor (TCR) alpha locus polymorphism as well as other immune regulatory loci. Increased incidence of narcolepsy was detected following the 2009 H1N1 pandemic and linked to Pandemrix ® vaccination, strongly supporting that narcolepsy is an autoimmune disorder. Although recent results suggest CD4+ T cell reactivity to neuropeptide hypocretin/orexin and cross-reactive flu peptide is involved, identification of other autoantigens has remained elusive. Here we study whether autoimmunity directed against Regulatory Factor X4 (RFX4), a protein co-localized with hypocretin, is involved in some cases. Studying human serum, we found that autoantibodies against RFX4 were rare. Using RFX4 peptides bound to DQ0602 tetramers, antigen RFX4-86,-95, and-60 specific human CD4+ T cells were detected in 4/10 patients and 2 unaffected siblings but not in others. Following culture with each cognate peptide, enriched autoreactive TCRαβ clones were isolated by single-cell sorting and TCR sequenced. Homologous clones bearing TRBV4-2 and recognizing RFX4-86 in patients and one twin control of patient were identified. These results suggest the involvement of RFX4 CD4+ T cell autoreactivity in some cases of narcolepsy.

scholarly journals Extending the CD4+ T-Cell Epitope Specificity of the Th1 Immune Response to an Antigen Using aSalmonella enterica Serovar Typhimurium Delivery Vehicle

2000 ◽  
Vol 68 (6) ◽  
pp. 3079-3089 ◽  
Author(s):  
Richard Lo-Man ◽  
Jan P. M. Langeveld ◽  
Edith Dériaud ◽  
Muguette Jehanno ◽  
Marie Rojas ◽  
...  
Keyword(s):  
T Cell ◽  
Mhc Class Ii ◽  
Cell Response ◽  
Cell Epitope ◽  
T Cell Response ◽  
Cd4 T Cell ◽  
Cell Repertoire ◽  
Cell Reactivity ◽  
Serovar Typhimurium ◽  
T Cell Reactivity

ABSTRACT We analyzed the CD4 T-cell immunodominance of the response to a model antigen (Ag), MalE, when delivered by an attenuated strain ofSalmonella enterica serovar Typhimurium (SL3261*pMalE). Compared to purified MalE Ag administered with adjuvant, the mapping of the peptide-specific proliferative responses showed qualitative differences when we used the Salmonella vehicle. We observed the disappearance of one out of eight MalE peptides' T-cell reactivity upon SL3261*pMalE immunization, but this phenomenon was probably due to a low level of T-cell priming, since it could be overcome by further immunization. The most striking effect of SL3261*pMalE administration was the activation and stimulation of new MalE peptide-specific T-cell responses that were silent after administration of purified Ag with adjuvant. Ag presentation assays performed with MalE-specific T-cell hybridomas showed that infection of Ag-presenting cells by this intracellular attenuated bacterium did not affect the processing and presentation of the different MalE peptides by major histocompatibility complex (MHC) class II molecules and therefore did not account for immunodominance modulation. Thus, immunodominance of the T-cell response to microorganisms is governed not only by the frequency of the available T-cell repertoire or the processing steps in Ag-presenting cells that lead to MHC presentation but also by other parameters probably related to the infectious process and to the bacterial products. Our results indicate that, upon infection by a microorganism, the specificity of the T-cell response induced against its Ags can be much more effective than with purified Ags and that it cannot completely be mimicked by purified Ags administered with adjuvant.

scholarly journals Enhanced influenza A H1N1 T cell epitope recognition and cross-reactivity to protein-O-mannosyltransferase 1 in Pandemrix-associated narcolepsy type 1

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
A. Vuorela ◽  
T. L. Freitag ◽  
K. Leskinen ◽  
H. Pessa ◽  
T. Härkönen ◽  
...  
Keyword(s):  
T Cell ◽  
Influenza A ◽  
Strong Association ◽  
Cell Epitope ◽  
Cell Receptor ◽  
Cross Reactivity ◽  
Cell Immunity ◽  
Increased Risk ◽  
Influenza A H1n1

AbstractNarcolepsy type 1 (NT1) is a chronic neurological disorder having a strong association with HLA-DQB1*0602, thereby suggesting an immunological origin. Increased risk of NT1 has been reported among children or adolescents vaccinated with AS03 adjuvant-supplemented pandemic H1N1 influenza A vaccine, Pandemrix. Here we show that pediatric Pandemrix-associated NT1 patients have enhanced T-cell immunity against the viral epitopes, neuraminidase 175–189 (NA175–189) and nucleoprotein 214–228 (NP214–228), but also respond to a NA175–189-mimic, brain self-epitope, protein-O-mannosyltransferase 1 (POMT1675–689). A pathogenic role of influenza virus-specific T-cells and T-cell cross-reactivity in NT1 are supported by the up-regulation of IFN-γ, perforin 1 and granzyme B, and by the converging selection of T-cell receptor TRAV10/TRAJ17 and TRAV10/TRAJ24 clonotypes, in response to stimulation either with peptide NA175–189 or POMT1675–689. Moreover, anti-POMT1 serum autoantibodies are increased in Pandemrix-vaccinated children or adolescents. These results thus identify POMT1 as a potential autoantigen recognized by T- and B-cells in NT1.

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