CD8 T cells recognize short peptides, more frequently of nine residues, presented by class I major histocompatibility complex (MHC I) molecules in the cell surface of antigen-presenting cells. These ...epitope peptides are loaded onto MHC I molecules in the endoplasmic reticulum, where they are shuttled from the cytosol by the transporter associated with antigen processing (TAP) as such or as N-terminal extended precursors of up to 16 residues. In this chapter, we describe the use of TAPREG, a tool for predicting TAP binding affinity that has been enhanced to identify potential CD8 T cell epitope precursors transported by TAP. TAPREG is available for free public use at http://imed.med.ucm.es/Tools/tapreg/ .
SARS-CoV-2 infection takes a mild or clinically inapparent course in the majority of humans who contract this virus. After such individuals have cleared the virus, only the detection of ...SARS-CoV-2-specific immunological memory can reveal the exposure, and hopefully the establishment of immune protection. With most viral infections, the presence of specific serum antibodies has provided a reliable biomarker for the exposure to the virus of interest. SARS-CoV-2 infection, however, does not reliably induce a durable antibody response, especially in sub-clinically infected individuals. Consequently, it is plausible for a recently infected individual to yield a false negative result within only a few months after exposure. Immunodiagnostic attention has therefore shifted to studies of specific T cell memory to SARS-CoV-2. Most reports published so far agree that a T cell response is engaged during SARS-CoV-2 infection, but they also state that in 20-81% of SARS-CoV-2-unexposed individuals, T cells respond to SARS-CoV-2 antigens (mega peptide pools), allegedly due to T cell cross-reactivity with Common Cold coronaviruses (CCC), or other antigens. Here we show that, by introducing irrelevant mega peptide pools as negative controls to account for chance cross-reactivity, and by establishing the antigen dose-response characteristic of the T cells, one can clearly discern between cognate T cell memory induced by SARS-CoV-2 infection vs. cross-reactive T cell responses in individuals who have not been infected with SARS-CoV-2.
infection causes Chagas disease, which affects 7 million people worldwide. Two drugs are available to treat it: benznidazole and nifurtimox. Although both are efficacious against the acute stage of ...the disease, this is usually asymptomatic and goes undiagnosed and untreated. Diagnosis is achieved at the chronic stage, when life-threatening heart and/or gut tissue disruptions occur in ~30% of those chronically infected. By then, the drugs' efficacy is reduced, but not their associated high toxicity. Given current deficiencies in diagnosis and treatment, a vaccine to prevent infection and/or the development of symptoms would be a breakthrough in the management of the disease. Current vaccine candidates are mostly based on the delivery of single antigens or a few different antigens. Nevertheless, due to the high biological complexity of the parasite, targeting as many antigens as possible would be desirable. In this regard, an epitope-based vaccine design could be a well-suited approach. With this aim, we have gone through publicly available databases to identify
epitopes from several antigens. By means of a computer-aided strategy, we have prioritized a set of epitopes based on sequence conservation criteria, projected population coverage of Latin American population, and biological features of their antigens of origin. Fruit of this analysis, we provide a selection of CD8
T cell, CD4
T cell, and B cell epitopes that have <70% identity to human or human microbiome protein sequences and represent the basis toward the development of an epitope-based vaccine against
.
The 2nd Computational Methods for the Immune System function Workshop has been held in Madrid in conjunction with the IEEE International Conference on Bioinformatics and Biomedicine (BIBM 2018) in ...Madrid, Spain, from December 3 to 6, 2018. The workshop has been obtained 100% more submissions in respect to the first edition, highlighting a growing interest for the treated topics. The best papers (9) have been selected for extension in this special issue, with themes about immune system and disease simulation, computer-aided design of novel candidate vaccines, methods for the analysis of immune system involved diseases based on statistical methods, meta-heuristics and game theory, and modelling strategies for improving the simulation of the immune system dynamics.
•We have designed an epitope ensemble vaccine targeting TB.•We have extended previous work to target specific antigens that dominate human immune responses.•We have estimated the level of population ...protection afforded by such an ensemble vaccine.•We have promulgated a putative global TB vaccine and one specific to endemic regions of East Africa.
Effective control of Mycobacterium tuberculosis is a global necessity. In 2015, tuberculosis (TB) caused more deaths than HIV. Considering the increasing prevalence of multi-drug resistant forms of M. tuberculosis, the need for effective TB vaccines becomes imperative. Currently, the only licensed TB vaccine is Bacillus Calmette-Guérin (BCG). Yet, BCG has many drawbacks limiting its efficacy and applicability. We applied advanced computational procedures to derive a universal TB vaccine and one targeting East Africa. Our approach selects an optimal set of highly conserved, experimentally validated epitopes, with high projected population coverage (PPC). Through rigorous data analysis, five different potential vaccine combinations were selected each with PPC above 80% for East Africa and above 90% for the World. Two potential vaccines only contained CD8+ epitopes, while the others included both CD4+ and CD8+ epitopes. Our prime vaccine candidate was a putative seven-epitope ensemble comprising: SRGWSLIKSVRLGNA, KPRIITLTMNPALDI, AAHKGLMNIALAISA, FPAGGSTGSL, MLLAVTVSL, QSSFYSDW and KMRCGAPRY, with a 97.4% global PPC and a 92.7% East African PPC.
Human Cytomegalovirus (HCMV) is a ubiquitous herpesvirus affecting approximately 90% of the world population. HCMV causes disease in immunologically naive and immunosuppressed patients. The ...prevention, diagnosis and therapy of HCMV infection are thus crucial to public health. The availability of effective prophylactic and therapeutic treatments remain a significant challenge and no vaccine is currently available. Here, we sought to define an epitope-based vaccine against HCMV, eliciting B and T cell responses, from experimentally defined HCMV-specific epitopes.
We selected 398 and 790 experimentally validated HCMV-specific B and T cell epitopes, respectively, from available epitope resources and apply a knowledge-based approach in combination with immunoinformatic predictions to ensemble a universal vaccine against HCMV. The T cell component consists of 6 CD8 and 6 CD4 T cell epitopes that are conserved among HCMV strains. All CD8 T cell epitopes were reported to induce cytotoxic activity, are derived from early expressed genes and are predicted to provide population protection coverage over 97%. The CD4 T cell epitopes are derived from HCMV structural proteins and provide a population protection coverage over 92%. The B cell component consists of just 3 B cell epitopes from the ectodomain of glycoproteins L and H that are highly flexible and exposed to the solvent.
We have defined a multiantigenic epitope vaccine ensemble against the HCMV that should elicit T and B cell responses in the entire population. Importantly, although we arrived to this epitope ensemble with the help of computational predictions, the actual epitopes are not predicted but are known to be immunogenic.
Immune Tolerance in the Oral Mucosa Pelaez-Prestel, Hector F; Sanchez-Trincado, Jose L; Lafuente, Esther M ...
International journal of molecular sciences,
11/2021, Volume:
22, Issue:
22
Journal Article
Peer reviewed
Open access
The oral mucosa is a site of intense immune activity, where a large variety of immune cells meet to provide a first line of defense against pathogenic organisms. Interestingly, the oral mucosa is ...exposed to a plethora of antigens from food and commensal bacteria that must be tolerated. The mechanisms that enable this tolerance are not yet fully defined. Many works have focused on active immune mechanisms involving dendritic and regulatory T cells. However, epithelial cells also make a major contribution to tolerance by influencing both innate and adaptive immunity. Therefore, the tolerogenic mechanisms concurring in the oral mucosa are intertwined. Here, we review them systematically, paying special attention to the role of oral epithelial cells.
Major histocompatibility complex class I (MHCI) and class II (MHCII) molecules display peptides on antigen-presenting cell surfaces for subsequent T-cell recognition. Within the human population, ...allelic variation among the classical MHCI and II gene products is the basis for differential peptide binding, thymic repertoire bias and allograft rejection. While available 3D structural analysis suggests that polymorphisms are found primarily within the peptide-binding site, a broader informatic approach pinpointing functional polymorphisms relevant for immune recognition is currently lacking. To this end, we have now analyzed known human class I (774) and class II (485) alleles at each amino acid position using a variability metric (
V). Polymorphisms (
V>1) have been identified in residues that contact the peptide and/or T-cell receptor (TCR). Using sequence logos to investigate TCR contact sites on HLA molecules, we have identified conserved MHCI residues distinct from those of conserved MHCII residues. In addition, specific class II (HLA-DP, -DQ, -DR) and class I (HLA-A, -B, -C) contacts for TCR binding are revealed. We discuss these findings in the context of TCR restriction and alloreactivity.
Initial molecular details of cellular activation following αβT cell antigen receptor (TCR) ligation by peptide-major histocompatibility complexes (pMHC) remain unexplored. We determined the nuclear ...magnetic resonance (NMR) structure of the TCRα subunit transmembrane (TM) domain revealing a bipartite helix whose segmentation fosters dynamic movement. Positively charged TM residues Arg251 and Lys256 project from opposite faces of the helix, with Lys256 controlling immersion depth. Their modification caused stepwise reduction in TCR associations with CD3ζζ homodimers and CD3εγ plus CD3εδ heterodimers, respectively, leading to an activated transcriptome. Optical tweezers revealed that Arg251 and Lys256 mutations altered αβTCR-pMHC bond lifetimes, while mutations within interacting TCRα connecting peptide and CD3δ CxxC motif juxtamembrane elements selectively attenuated signal transduction. Our findings suggest that mechanical forces applied during pMHC ligation initiate T cell activation via a dissociative mechanism, shifting disposition of those basic sidechains to rearrange TCR complex membrane topology and weaken TCRαβ and CD3 associations.
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•The TCRα transmembrane (TM) domain is a bipartite helix separated by a dynamic hinge•Lys256 controls the TCRαTM depth and CD3 homo- and heterodimer associations•The TCRα- and CD3δ-juxtamembrane elements mediate a specific TCRα-CD3δ interaction•Key residues within TCRαTM or juxtamembrane domains govern αβTCR mechanotransduction
While TCR triggering is critical for adaptive immunity, how bioforces accompanying ligand binding transduce signals through the cell membrane is unknown. Brazin et al. define dynamic structural movements within the TCRα transmembrane domain linked to fundamental TCR complex mechanobiology, including subunit topological rearrangements that foster dissociation of CD3 dimers and cell activation.
EPIPOX is a specialized online resource intended to facilitate the design of epitope-based vaccines against orthopoxviruses. EPIPOX is built upon a collection of T cell epitopes that are shared by ...eight pathogenic orthopoxviruses, including variola minor and major strains, monkeypox, cowpox, and vaccinia viruses. In EPIPOX, users can select T cell epitopes attending to the predicted binding to distinct major histocompatibility molecules (MHC) and according to various features that may have an impact on epitope immunogenicity. Among others, EPIPOX allows to discern epitopes by their structural location in the virion and the temporal expression of the counterpart antigens. Overall, the annotations in EPIPOX are optimized to facilitate the rational design of T cell epitope-based vaccines. In this chapter, we describe the main features of EPIPOX and exemplify its use, retrieving orthopoxvirus-specific T cell epitopes with features set to enhance their immunogenicity. EPIPOX is available for free public use at http://bio.med.ucm.es/epipox/ .
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