T-cell deficiency and hyperinflammatory monocyte responses associate with complex lung disease.

Immunological mechanisms of susceptibility to nontuberculous mycobacterial (NTM) disease are poorly understood. To understand NTM pathogenesis, we evaluated innate and antigen-specific adaptive immune responses to complex (MAC) in asymptomatic individuals with a previous history of MAC lung disease (MACDZ). We hypothesized that Mav-specific immune responses are associated with susceptibility to MAC lung disease.

Allele-Specific Thresholds of Eluted Ligands for T-Cell Epitope Prediction.

A common strategy for predicting candidate human leukocyte antigen class I T-cell epitopes is to use an affinity-based threshold of 500 nM. Although a 500 nM threshold across alleles effectively identifies most epitopes across alleles, findings showing that major histocompatibility complex repertoire sizes vary by allele indicate that using thresholds specific to individual alleles may improve epitope identification. In this work, we compare different strategies utilizing common and allele-specific thresholds to identify an optimal approach for T-cell epitope prediction.

An Immunomodulatory Therapeutic Vaccine Targeting Oligomeric Amyloid-β.

Background: Aging is considered the most important risk factor for Alzheimer's disease (AD). Recent research supports the theory that immunotherapy targeting the "oligomeric" forms of amyloid-β (Aβ) may halt the progression of AD. However, previous clinical trial of the vaccine against Aβ, called AN1792, was suspended due to cases of meningoencephalitis in patients.

Benchmarking predictions of MHC class I restricted T cell epitopes in a comprehensively studied model system.

T cell epitope candidates are commonly identified using computational prediction tools in order to enable applications such as vaccine design, cancer neoantigen identification, development of diagnostics and removal of unwanted immune responses against protein therapeutics. Most T cell epitope prediction tools are based on machine learning algorithms trained on MHC binding or naturally processed MHC ligand elution data. The ability of currently available tools to predict T cell epitopes has not been comprehensively evaluated.

NetMHCpan-4.1 and NetMHCIIpan-4.0: improved predictions of MHC antigen presentation by concurrent motif deconvolution and integration of MS MHC eluted ligand data.

Major histocompatibility complex (MHC) molecules are expressed on the cell surface, where they present peptides to T cells, which gives them a key role in the development of T-cell immune responses. MHC molecules come in two main variants: MHC Class I (MHC-I) and MHC Class II (MHC-II). MHC-I predominantly present peptides derived from intracellular proteins, whereas MHC-II predominantly presents peptides from extracellular proteins.

Major Histocompatibility Complex Binding, Eluted Ligands, and Immunogenicity: Benchmark Testing and Predictions.

Antidrug antibody (ADA) responses impact drug safety, potency, and efficacy. It is generally assumed that ADA responses are associated with human leukocyte antigen (HLA) class II-restricted CD4+ T-cell reactivity. Although this review does not address ADA responses , the analysis presented here is relevant to the topic, because measuring or predicting CD4+ T-cell reactivity is a common strategy to address ADA and immunogenicity concerns.

IEDB-AR: immune epitope database-analysis resource in 2019.

The Immune Epitope Database Analysis Resource (IEDB-AR, http://tools.iedb.org/) is a companion website to the IEDB that provides computational tools focused on the prediction and analysis of B and T cell epitopes.

Poor Antigen Processing of Poxvirus Particles Limits CD4 T Cell Recognition and Impacts Immunogenicity of the Inactivated Vaccine.

CD4 T cells play critical roles in defending against poxviruses, both by potentiating cellular and humoral responses and by directly killing infected cells. Despite this central role, the basis for pox-specific CD4 T cell activation, specifically the origin of the poxvirus-derived peptides (epitopes) that activate CD4 T cells, remains poorly understood. In addition, because the current licensed poxvirus vaccines can cause serious adverse events and even death, elucidating the requirements for MHC class II (MHC-II) processing and presentation of poxviral Ags could be of great use.

A Review on T Cell Epitopes Identified Using Prediction and Cell-Mediated Immune Models for and .

In the present review, we summarize work from our as well as other groups related to the characterization of bacterial T cell epitopes, with a specific focus on two important pathogens, namely, (), the bacterium that causes tuberculosis (TB), and (BP), the bacterium that causes whooping cough. Both bacteria and their associated diseases are of large societal significance. Although vaccines exist for both pathogens, their efficacy is incomplete.

Footprints of antigen processing boost MHC class II natural ligand predictions.

Background: Major histocompatibility complex class II (MHC-II) molecules present peptide fragments to T cells for immune recognition. Current predictors for peptide to MHC-II binding are trained on binding affinity data, generated in vitro and therefore lacking information about antigen processing.

Methods: We generate prediction models of peptide to MHC-II binding trained with naturally eluted ligands derived from mass spectrometry in addition to peptide binding affinity data sets.

Determination of a Predictive Cleavage Motif for Eluted Major Histocompatibility Complex Class II Ligands.

CD4 T cells have a major role in regulating immune responses. They are activated by recognition of peptides mostly generated from exogenous antigens through the major histocompatibility complex (MHC) class II pathway. Identification of epitopes is important and computational prediction of epitopes is used widely to save time and resources.

Predicting HLA CD4 Immunogenicity in Human Populations.

Background: Prediction of T cell immunogenicity is a topic of considerable interest, both in terms of basic understanding of the mechanisms of T cells responses and in terms of practical applications. HLA binding affinity is often used to predict T cell epitopes, since HLA binding affinity is a key requisite for human T cell immunogenicity. However, immunogenicity at the population it is complicated by the high level of variability of HLA molecules, potential other factors beyond HLA as well as the frequent lack of HLA typing data.

Allergen and Epitope Targets of Mouse-Specific T Cell Responses in Allergy and Asthma.

Mouse allergy has become increasingly common, mainly affecting laboratory workers and inner-city households. To date, only one major allergen, namely Mus m 1, has been described. We sought to identify T cell targets in mouse allergic patients.

Correction: Definition of Human Epitopes Recognized in Tetanus Toxoid and Development of an Assay Strategy to Detect Ex Vivo Tetanus CD4+ T Cell Responses.

[This corrects the article DOI: 10.1371/journal.pone.

Influenza-derived peptides cross-react with allergens and provide asthma protection.

Background: The hygiene hypothesis is the leading concept to explain the current asthma epidemic, which is built on the observation that a lack of bacterial contact early in life induces allergic T2 immune responses.

Objective: Because little is known about the contribution of respiratory tract viruses in this context, we evaluated the effect of prior influenza infection on the development of allergic asthma.

Methods: Mice were infected with influenza and, once recovered, subjected to an ovalbumin- or house dust mite-induced experimental asthma protocol.

NetMHCpan-4.0: Improved Peptide-MHC Class I Interaction Predictions Integrating Eluted Ligand and Peptide Binding Affinity Data.

Cytotoxic T cells are of central importance in the immune system's response to disease. They recognize defective cells by binding to peptides presented on the cell surface by MHC class I molecules. Peptide binding to MHC molecules is the single most selective step in the Ag-presentation pathway.

Experimental validation of the RATE tool for inferring HLA restrictions of T cell epitopes.

Background: The RATE tool was recently developed to computationally infer the HLA restriction of given epitopes from immune response data of HLA typed subjects without additional cumbersome experimentation.

Results: Here, RATE was validated using experimentally defined restriction data from a set of 191 tuberculosis-derived epitopes and 63 healthy individuals with MTB infection from the Western Cape Region of South Africa. Using this experimental dataset, the parameters utilized by the RATE tool to infer restriction were optimized, which included relative frequency (RF) of the subjects responding to a given epitope and expressing a given allele as compared to the general test population and the associated p-value in a Fisher's exact test.

The Immune Epitope Database and Analysis Resource in Epitope Discovery and Synthetic Vaccine Design.

The task of epitope discovery and vaccine design is increasingly reliant on bioinformatics analytic tools and access to depositories of curated data relevant to immune reactions and specific pathogens. The Immune Epitope Database and Analysis Resource (IEDB) was indeed created to assist biomedical researchers in the development of new vaccines, diagnostics, and therapeutics. The Analysis Resource is freely available to all researchers and provides access to a variety of epitope analysis and prediction tools.

Patterns of Cellular Immunity Associated with Experimental Infection with rDEN2Δ30 (Tonga/74) Support Its Suitability as a Human Dengue Virus Challenge Strain.

A deletion variant of the dengue virus (DENV) serotype 2 (DENV2) Tonga/74 strain lacking 30 nucleotides from its 3' untranslated region (rDEN2Δ30) has previously been established for use in a controlled human DENV challenge model. To evaluate if this model is appropriate for the derivation of correlates of protection for DENV vaccines on the basis of cellular immunity, we wanted to compare the cellular immune response to this challenge strain to the response induced by natural infection. To achieve this, we predicted HLA class I- and class II-restricted peptides from rDEN2Δ30 and used them in a gamma interferon enzyme-linked immunosorbent spot assay to interrogate CD8 and CD4 T cell responses in healthy volunteers infected with rDEN2Δ30.

Identification of Mycobacterial RplJ/L10 and RpsA/S1 Proteins as Novel Targets for CD4 T Cells.

Tuberculosis (TB) due to remains a major global infectious disease problem, and a more efficacious vaccine is urgently needed for the control and prevention of disease caused by this organism. We previously reported that a genetically modified strain of called IKEPLUS is a promising TB vaccine candidate. Since protective immunity induced by IKEPLUS is dependent on antigen-specific CD4 T cell memory, we hypothesized that the specificity of the CD4 T cell response was a critical feature of this protection.

Definition of Human Epitopes Recognized in Tetanus Toxoid and Development of an Assay Strategy to Detect Ex Vivo Tetanus CD4+ T Cell Responses.

Despite widespread uses of tetanus toxoid (TT) as a vaccine, model antigen and protein carrier, TT epitopes have been poorly characterized. Herein we defined the human CD4+ T cell epitope repertoire by reevaluation of previously described epitopes and evaluation of those derived from prediction of HLA Class II binding. Forty-seven epitopes were identified following in vitro TT stimulation, with 28 epitopes accounting for 90% of the total response.