Review

Authors: Paul A Roche, Kazuyuki Furuta

Antigenic peptide-loaded MHC class II molecules (peptide-MHC class II) are constitutively expressed on the surface of professional antigen-presenting cells (APCs), including dendritic cells, B cells, macrophages and thymic epithelial cells, and are presented to antigen-specific CD4(+) T cells. The mechanisms of antigen uptake, the nature of the antigen processing compartments and the lifetime of cell surface peptide-MHC class II complexes can vary depending on the type of APC. It is likely that these differences are important for the function of each distinct APC subset in the generation of effective adaptive immune responses. In this Review, we describe our current knowledge of the mechanisms of uptake and processing of antigens, the intracellular formation of peptide-MHC class II complexes, the intracellular trafficking of peptide-MHC class II complexes to the APC plasma membrane and their ultimate degradation.

Topics: Animals; Antigen Presentation; Antigen-Presenting Cells; Antigens; Cell Membrane; Epitopes; Histocompatibility Antigens Class II; Humans; Peptides; Protein Transport

PubMed: 25720354
DOI: 10.1038/nri3818

Authors: Assaf Kacen, Aaron Javitt, Matthias P Kramer...

Post-translational modification (PTM) of antigens provides an additional source of specificities targeted by immune responses to tumors or pathogens, but identifying antigen PTMs and assessing their role in shaping the immunopeptidome is challenging. Here we describe the Protein Modification Integrated Search Engine (PROMISE), an antigen discovery pipeline that enables the analysis of 29 different PTM combinations from multiple clinical cohorts and cell lines. We expanded the antigen landscape, uncovering human leukocyte antigen class I binding motifs defined by specific PTMs with haplotype-specific binding preferences and revealing disease-specific modified targets, including thousands of new cancer-specific antigens that can be shared between patients and across cancer types. Furthermore, we uncovered a subset of modified peptides that are specific to cancer tissue and driven by post-translational changes that occurred in the tumor proteome. Our findings highlight principles of PTM-driven antigenicity, which may have broad implications for T cell-mediated therapies in cancer and beyond.

Topics: Humans; Protein Processing, Post-Translational; Peptides; Antigens; Histocompatibility Antigens Class I; Neoplasms

PubMed: 36203013
DOI: 10.1038/s41587-022-01464-2

Review

Authors: Janett Göhring, Lukas Schrangl, Gerhard J Schütz...

Efficient scanning of tissue that T cells encounter during their migratory life is pivotal to protective adaptive immunity. In fact, T cells can detect even a single antigenic peptide/MHC complex (pMHC) among thousands of structurally similar yet non-stimulatory endogenous pMHCs on the surface of antigen-presenting cells (APCs) or target cells. Of note, the glycocalyx of target cells, being composed of proteoglycans and bulky proteins, is bound to affect and even modulate antigen recognition by posing as a physical barrier. T cell-resident microvilli are actin-rich membrane protrusions that puncture through such barriers and thereby actively place the considerably smaller T-cell antigen receptors (TCRs) in close enough proximity to APC-presented pMHCs so that productive interactions may occur efficiently yet under force. We here review our current understanding of how the plasticity of T-cell microvilli and physicochemical properties of the glycocalyx may affect early events in T-cell activation. We assess insights gained from studies on T-cell plasma membrane ultrastructure and provide an update on current efforts to integrate biophysical aspects such as the amplitude and directionality of TCR-imposed mechanical forces and the distribution and lateral mobility of plasma membrane-resident signaling molecules into a more comprehensive view on sensitized T-cell antigen recognition.

Topics: Antigen-Presenting Cells; Antigens; Lymphocyte Activation; Protein Binding; Receptors, Antigen, T-Cell; T-Lymphocytes

PubMed: 35693808
DOI: 10.3389/fimmu.2022.886328

Review

Authors: Scheherazade Sadegh-Nasseri, AeRyon Kim

MHC II proteins present processed antigens to CD4 + T cells through a complex set of events and players that include chaperons and accessory molecules. Antigen processing machinery is optimized for the selection of the best fitting peptides, called 'immunodominant epitopes', in the MHC II groove to which, specific CD4 + T cells respond and differentiate into memory T cells. However, due to the complexity of antigen processing, understanding the parameters that lead to immunodominance has proved difficult. Moreover, immunodominance of epitopes vary, depending on multiple factors that include; simultaneous processing of multiple proteins, involvement of multiple alleles of MHC II that can bind to the same antigen, or competition among several suitable epitopes on a single protein antigen. The current dogma assumes that once an antigenic determinant is selected under a specific condition, it would emerge immunodominant wherever it is placed. Here we will discuss some established parameters that contribute to immunodominance as well as some new findings, which demonstrate that slight changes to antigen structure can cause a complete shift in epitope selection during antigen processing and distort the natural immunodominant epitope.

Topics: Animals; Antigen Presentation; Antigen-Presenting Cells; Antigens; CD4-Positive T-Lymphocytes; Epitopes; Histocompatibility Antigens Class II; Humans; Immunodominant Epitopes; Immunologic Memory; Peptides

PubMed: 30146122
DOI: 10.1016/j.molimm.2018.08.011

Authors: Jing Guo, Roshni Roy Chowdhury, Vamsee Mallajosyula...

γδ T cells are essential for immune defense and modulating physiological processes. While they have the potential to recognize large numbers of antigens through somatic gene rearrangement, the antigens which trigger most γδ T cell response remain unidentified, and the role of antigen recognition in γδ T cell function is contentious. Here, we show that some γδ T cell receptors (TCRs) exhibit polyspecificity, recognizing multiple ligands of diverse molecular nature. These ligands include haptens, metabolites, neurotransmitters, posttranslational modifications, as well as peptides and proteins of microbial and host origin. Polyspecific γδ T cells are enriched among activated cells in naive mice and the responding population in infection. They express diverse TCR sequences, have different functional potentials, and include the innate-like γδ T cells, such as the major IL-17 responders in various pathological/physiological conditions. We demonstrate that encountering their antigenic microbiome metabolite maintains their homeostasis and functional response, indicating that their ability to recognize multiple ligands is essential for their function. Human γδ T cells with similar polyspecificity also respond to various immune challenges. This study demonstrates that polyspecificity is a prevalent feature of γδ T cell antigen recognition, which enables rapid and robust T cell responses to a wide range of challenges, highlighting a unique function of γδ T cells.

Topics: Humans; Mice; Animals; Receptors, Antigen, T-Cell, gamma-delta; Antigens; Haptens; Blood Group Antigens

PubMed: 38227652
DOI: 10.1073/pnas.2315592121

Review

Authors: Y A Knirel, Qiangzheng Sun, S N Senchenkova...

O-Antigens (O-specific polysaccharides) of Shigella flexneri, a primary cause of shigellosis, are distinguished by a wide diversity of chemical modifications following the oligosaccharide O-unit assembly. The present review is devoted to structural, serological, and genetic aspects of these modifications, including O-acetylation and phosphorylation with phosphoethanolamine that have been identified recently. The modifications confer the host with specific immunodeterminants (O-factors or O-antigen epitopes), which accounts for the antigenic diversity of S. flexneri considered as a virulence factor of the pathogen. Totally, 30 O-antigen variants have been recognized in these bacteria, the corresponding O-factors characterized using specific antibodies, and a significant extension of the serotyping scheme of S. flexneri on this basis is suggested. Multiple genes responsible for the O-antigen modifications and the resultant serotype conversions of S. flexneri have been identified. The genetic mechanisms of the O-antigen diversification by acquisition of mobile genetic elements, including prophages and plasmids, followed occasionally by gene mobilization and inactivation have been revealed. These findings further our understanding of the genetics and antigenicity of S. flexneri and assist control of shigellosis.

Topics: Antigenic Variation; Epitopes; O Antigens; Oligosaccharides; Plasmids; Serotyping; Shigella flexneri

PubMed: 26542003
DOI: 10.1134/S0006297915070093

Review

Authors: Camila R R Barbosa, Justin Barton, Adrian J Shepherd...

Throughout its evolution, the human immune system has developed a plethora of strategies to diversify the antigenic peptide sequences that can be targeted by the CD8+ T cell response against pathogens and aberrations of self. Here we provide a general overview of the mechanisms that lead to the diversity of antigens presented by MHC class I complexes and their recognition by CD8+ T cells, together with a more detailed analysis of recent progress in two important areas that are highly controversial: the prevalence and immunological relevance of unconventional antigen peptides; and cross-recognition of antigenic peptides by the T cell receptors of CD8+ T cells.

Topics: Animals; Antigens; CD8-Positive T-Lymphocytes; Histocompatibility Antigens Class I; Humans; Models, Immunological; Peptides; Receptors, Antigen, T-Cell

PubMed: 34940832
DOI: 10.1042/BCJ20200910

Review

Authors: Satomi Ando, Koichi Araki

Persistent antigenic stimulation results in loss of effector function or physical deletion of antigen-specific CD8 T cells. This T-cell state is called T-cell exhaustion and occurs during chronic infection and cancer. Antigen-specific CD8 T cells during T-cell exhaustion express the inhibitory receptor PD-1, the expression of which plays a major role in T-cell dysfunction. PD-1 blockade re-invigorates CD8 T-cell immunity and has been proven effective against many different types of human cancer. To further improve the efficacy of PD-1-targeted immunotherapy in cancer patients, a better understanding of T-cell exhaustion is required. Recent studies have revealed that antigen-specific CD8 T cells during T-cell exhaustion are heterogeneous and have also uncovered the detailed mechanisms for PD-1-targeted immunotherapy. Here, we review the CD8 T-cell subsets that arise during T-cell exhaustion, the lineage relationship among these individual subsets and the role of each subset in PD-1 blockade. Also, we discuss potential strategies to enhance the efficacy of PD-1-targeted immunotherapy.

Topics: Antigens; CD8-Positive T-Lymphocytes; Humans; Immunologic Factors; Immunotherapy; Neoplasms; Programmed Cell Death 1 Receptor; T-Lymphocyte Subsets

PubMed: 35901837
DOI: 10.1093/intimm/dxac038

Review

Authors: Daniel W Kulp, William R Schief

Despite the tremendous successes of current vaccines, infectious diseases still take a heavy toll on the global population, and that provides strong rationale for broadening our vaccine development repertoire. Structural vaccinology, in which protein structure information is utilized to design immunogens, has promise to provide new vaccines against traditionally difficult targets. Crystal structures of antigens containing one or more protection epitopes, especially when in complex with a protective antibody, are the launching point for immunogen design. Integrating structure and sequence information for families of broadly neutralizing antibodies (bNAbs) has recently enabled the creation of germline-targeting immunogens that bind and activate germline B-cells in order to initiate the elicitation of such antibodies. The contacts between antigen and neutralizing antibody define a structural epitope, and methods have been developed to transplant epitopes to scaffold proteins for structural stabilization, and to design minimized antigens that retain one or more key epitopes while eliminating other potentially distracting or unnecessary features. To develop vaccines that protect against antigenically variable pathogens, pioneering structure-based work demonstrated that multiple strain-specific epitopes could be engineered onto a single immunogen. We review these recent structural vaccinology efforts to engineer germline-targeting, epitope-specific, and/or broad coverage immunogens.

Topics: Antibodies, Neutralizing; Antigens; Drug Discovery; Epitopes; Humans; Protein Engineering; Vaccines

PubMed: 23806515
DOI: 10.1016/j.coviro.2013.05.010

Review

Authors: David B Olawade, Jennifer Teke, Oluwaseun Fapohunda...

Vaccine development stands as a cornerstone of public health efforts, pivotal in curbing infectious diseases and reducing global morbidity and mortality. However, traditional vaccine development methods are often time-consuming, costly, and inefficient. The advent of artificial intelligence (AI) has ushered in a new era in vaccine design, offering unprecedented opportunities to expedite the process. This narrative review explores the role of AI in vaccine development, focusing on antigen selection, epitope prediction, adjuvant identification, and optimization strategies. AI algorithms, including machine learning and deep learning, leverage genomic data, protein structures, and immune system interactions to predict antigenic epitopes, assess immunogenicity, and prioritize antigens for experimentation. Furthermore, AI-driven approaches facilitate the rational design of immunogens and the identification of novel adjuvant candidates with optimal safety and efficacy profiles. Challenges such as data heterogeneity, model interpretability, and regulatory considerations must be addressed to realize the full potential of AI in vaccine development. Integrating emerging technologies, such as single-cell omics and synthetic biology, promises to enhance vaccine design precision and scalability. This review underscores the transformative impact of AI on vaccine development and highlights the need for interdisciplinary collaborations and regulatory harmonization to accelerate the delivery of safe and effective vaccines against infectious diseases.

Topics: Artificial Intelligence; Humans; Vaccine Development; Vaccines; Adjuvants, Immunologic; Epitopes; Animals; Antigens; Machine Learning

PubMed: 39019262
DOI: 10.1016/j.mimet.2024.106998