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International Review of Cell and... 2019Dendritic cells are at the center of immune responses. They are defined by their ability to sense the environment, take up and process antigen, migrate to secondary... (Review)
Review
Dendritic cells are at the center of immune responses. They are defined by their ability to sense the environment, take up and process antigen, migrate to secondary lymphoid organs, where they present antigens to the adaptive immune system. In particular, they present lipids and proteins from pathogens, which they encountered in peripheral tissues, to T cells in order to induce a specific effector immune response. These complex antigens need to be broken down into peptides of a certain length in association with Major Histocompatibility Complex (MHC) molecules. Presentation of MHC/antigen complexes alongside costimulatory molecules and secretion of proinflammatory cytokines will induce an appropriate immune response. This interaction between dendritic cells and T cells takes place at defined locations within secondary lymphoid organs. In this review, we discuss the current knowledge and recent advances on the cellular and molecular mechanisms that underlie antigen processing and the subsequent presentation to T lymphocytes.
Topics: Animals; Antigen Presentation; Dendritic Cells; Humans; Neoplasms
PubMed: 31810556
DOI: 10.1016/bs.ircmb.2019.07.005 -
Nature Reviews. Clinical Oncology Sep 2023Over the past decade, the emergence of effective immunotherapies has revolutionized the clinical management of many types of cancers. However, long-term durable tumour... (Review)
Review
Over the past decade, the emergence of effective immunotherapies has revolutionized the clinical management of many types of cancers. However, long-term durable tumour control is only achieved in a fraction of patients who receive these therapies. Understanding the mechanisms underlying clinical response and resistance to treatment is therefore essential to expanding the level of clinical benefit obtained from immunotherapies. In this Review, we describe the molecular mechanisms of antigen processing and presentation in tumours and their clinical consequences. We examine how various aspects of the antigen-presentation machinery (APM) shape tumour immunity. In particular, we discuss genomic variants in HLA alleles and other APM components, highlighting their influence on the immunopeptidomes of both malignant cells and immune cells. Understanding the APM, how it is regulated and how it changes in tumour cells is crucial for determining which patients will respond to immunotherapy and why some patients develop resistance. We focus on recently discovered molecular and genomic alterations that drive the clinical outcomes of patients receiving immune-checkpoint inhibitors. An improved understanding of how these variables mediate tumour-immune interactions is expected to guide the more precise administration of immunotherapies and reveal potentially promising directions for the development of new immunotherapeutic approaches.
Topics: Humans; Antigen Presentation; Neoplasms; Immunotherapy
PubMed: 37328642
DOI: 10.1038/s41571-023-00789-4 -
Frontiers in Immunology 2022The lungs are constantly exposed to environmental and infectious agents such as dust, viruses, fungi, and bacteria that invade the lungs upon breathing. The lungs are... (Review)
Review
The lungs are constantly exposed to environmental and infectious agents such as dust, viruses, fungi, and bacteria that invade the lungs upon breathing. The lungs are equipped with an immune defense mechanism that involves a wide variety of immunological cells to eliminate these agents. Various types of dendritic cells (DCs) and macrophages (MACs) function as professional antigen-presenting cells (APCs) that engulf pathogens through endocytosis or phagocytosis and degrade proteins derived from them into peptide fragments. During this process, DCs and MACs present the peptides on their major histocompatibility complex class I (MHC-I) or MHC-II protein complex to naïve CD8 or CD4 T cells, respectively. In addition to these cells, recent evidence supports that antigen-specific effector and memory T cells are activated by other lung cells such as endothelial cells, epithelial cells, and monocytes through antigen presentation. In this review, we summarize the molecular mechanisms of antigen presentation by APCs in the lungs and their contribution to immune response.
Topics: Antigen Presentation; Cells, Cultured; Dendritic Cells; Endothelial Cells; Lung
PubMed: 35615351
DOI: 10.3389/fimmu.2022.860915 -
Journal For Immunotherapy of Cancer Aug 2020Knowledge about and identification of T cell tumor antigens may inform the development of T cell receptor-engineered adoptive cell transfer or personalized cancer... (Review)
Review
BACKGROUND
Knowledge about and identification of T cell tumor antigens may inform the development of T cell receptor-engineered adoptive cell transfer or personalized cancer vaccine immunotherapy. Here, we review antigen processing and presentation and discuss limitations in tumor antigen prediction approaches.
METHODS
Original articles covering antigen processing and presentation, epitope discovery, and in silico T cell epitope prediction were reviewed.
RESULTS
Natural processing and presentation of antigens is a complex process that involves proteasomal proteolysis of parental proteins, transportation of digested peptides into the endoplasmic reticulum, loading of peptides onto major histocompatibility complex (MHC) class I molecules, and shuttling of peptide:MHC complexes to the cell surface. A number of T cell tumor antigens have been experimentally validated in patients with cancer. Assessment of predicted MHC class I binding and total score for these validated T cell antigens demonstrated a wide range of values, with nearly one-third of validated antigens carrying an IC of greater than 500 nM.
CONCLUSIONS
Antigen processing and presentation is a complex, multistep process. In silico epitope prediction techniques can be a useful tool, but comprehensive experimental testing and validation on a patient-by-patient basis may be required to reliably identify T cell tumor antigens.
Topics: Antigen Presentation; Female; Humans; Immunotherapy; Male; Neoplasms
PubMed: 32859742
DOI: 10.1136/jitc-2020-001111 -
Cellular Immunology May 2019Autoimmune diseases are heterogeneous group of disorders that together represent an enormous societal and medical problem. CD4+ T cells have critical roles in the... (Review)
Review
Autoimmune diseases are heterogeneous group of disorders that together represent an enormous societal and medical problem. CD4+ T cells have critical roles in the initiation and pathogenesis of autoimmune disease. As such, modulation of T cell activity has proven to have significant therapeutic effects in multiple autoimmune settings. T cell activation is a complex process with multiple potential therapeutic targets, many of which have been successfully utilized to treat human disease. Current pharmacological treatment largely targets T cell intrinsic activities as a means of treating various autoimmune disorders. Here I review extant and potential therapeutic approaches that instead specifically target antigen presentation to CD4+ T cells as a critical checkpoint in autoimmune responses. In addition, the contribution of antigen modulation components in current therapeutic approaches is considered along with the impact of new antigen targeted treatment modalities. Finally, potential challenges are considered in the context of the potential for antigen specific targeting of the antigen presentation process.
Topics: Animals; Antigen Presentation; Antigens; Autoimmune Diseases; Autoimmunity; CD4-Positive T-Lymphocytes; Humans
PubMed: 30554782
DOI: 10.1016/j.cellimm.2018.12.006 -
Current Opinion in Immunology Feb 2001Dendritic cells are the most efficient antigen-presenting cells. They take up antigens and pathogens, generate MHC-peptide complexes, migrate from the sites of antigen... (Review)
Review
Dendritic cells are the most efficient antigen-presenting cells. They take up antigens and pathogens, generate MHC-peptide complexes, migrate from the sites of antigen acquisition to secondary lymphoid organs and, finally, they physically interact with and stimulate T lymphocytes. Indeed, dendritic cells are the only antigen-presenting cells that induce the activation of resting T cells, both in vitro and in vivo. Thus, dendritic cells initiate adaptive immune responses and determine tolerance. To do so, dendritic cells have developed unique membrane transport pathways. The molecular mechanisms responsible for the control of antigen uptake and processing, for the generation of MHC-peptide complexes and for their transport to the cell surface have been partially unraveled in the past two years.
Topics: Animals; Antigen Presentation; Antigen-Presenting Cells; Dendritic Cells; Humans
PubMed: 11154916
DOI: 10.1016/s0952-7915(00)00180-1 -
Immunogenetics Mar 2019Immune response to disease requires coordinated expression of an army of molecules. The highly polymorphic MHC class I and class II molecules are key to control of... (Review)
Review
Immune response to disease requires coordinated expression of an army of molecules. The highly polymorphic MHC class I and class II molecules are key to control of specificity of antigen presentation. Processing of the antigen, to peptides or other moieties, requires other sets of molecules. For classical class I, this includes TAP peptide transporters, proteasome components and Tapasin, genes which are encoded within the MHC. Similarly, HLA-DO and -DM, which influence presentation by HLA class II molecules, are encoded in the MHC region. Analysis of MHC mutants, including point mutations and large deletions, has been central to understanding the roles of these genes. Mouse genetics has also played a major role. Many other genes have been identified including those controlling expression of HLA class I and class II at the transcriptional level. Another genetic approach that has provided insight has been the analysis of microorganisms, including viruses and bacteria that escape immune recognition by blocking these antigen processing and presentation pathways. Here, we provide a brief history of the genetic approaches, both traditional and modern, that have been used in the quest to understand antigen processing and presentation.
Topics: Animals; Antigen Presentation; Humans; Immunogenetics; Major Histocompatibility Complex
PubMed: 30215098
DOI: 10.1007/s00251-018-1082-2 -
Current Opinion in Immunology Jun 2021Current treatments for autoimmune diseases do not address the immune pathology underlying their initiation and progression and too often rely on non-specific... (Review)
Review
Current treatments for autoimmune diseases do not address the immune pathology underlying their initiation and progression and too often rely on non-specific immunosuppressive drugs for control of symptoms. Antigen-specific immunotherapy aims to induce tolerance selectively among the cells causing the disease while leaving the rest of the adaptive immune system capable of protecting against infectious diseases and cancers. Here we describe how novel approaches for antigen-specific immunotherapy are designed to manipulate antigen presentation and promote tolerance to specific self-antigens. This analysis points to liver antigen presenting cells, targeted by carrier particles, and steady-state dendritic cells, to which antigen-processing independent T-cell epitopes (apitopes) bind directly, as the principal targets for antigen-specific immunotherapy. Delivery of antigens to these cells holds great promise for effective control of this rapidly expanding group of diseases.
Topics: Animals; Antigen Presentation; Antigen-Presenting Cells; Autoimmune Diseases; Humans
PubMed: 33878516
DOI: 10.1016/j.coi.2021.03.019 -
The Journal of Investigative Dermatology Mar 2022Autoreactive T cells pose a constant risk for the emergence of autoimmune skin diseases in genetically predisposed individuals carrying certain HLA risk alleles. Immune... (Review)
Review
Autoreactive T cells pose a constant risk for the emergence of autoimmune skin diseases in genetically predisposed individuals carrying certain HLA risk alleles. Immune tolerance mechanisms are opposed by broad HLA-presented self-immunopeptidomes, a predefined repertoire of polyspecific TCRs, the continuous generation of new antibody specificities by somatic recombination of Ig genes in B cells, and heightened proinflammatory reactivity. Increased autoantigen presentation by HLA molecules, cross-activation of pathogen-induced T cells against autologous structures, altered metabolism of self-proteins, and excessive production of proinflammatory signals may all contribute to the breakdown of immune tolerance and the development of autoimmune skin diseases.
Topics: Antigen Presentation; Autoantigens; Autoimmune Diseases; Humans; Immune Tolerance; Receptors, Antigen, T-Cell; Skin Diseases
PubMed: 34294386
DOI: 10.1016/j.jid.2021.05.009 -
Neurotherapeutics : the Journal of the... Oct 2016Stroke induces a local inflammatory reaction and a plethora of innate immune responses in the brain where antigen-presenting cells become prominent. However, to date, it... (Review)
Review
Stroke induces a local inflammatory reaction and a plethora of innate immune responses in the brain where antigen-presenting cells become prominent. However, to date, it is still unclear whether antigen presentation is relevant to the neuropathological and functional outcome of stroke. Stroke does not trigger overt autoimmune reactions, but neural antigens have been found in lymphoid tissues of patient with stroke and it is unknown whether they promote tolerance or immune reactions that under certain conditions might contribute to the functional worsening observed in some patients. Autoantibodies to neural molecules have also been reported in patients with stroke, but the subclass of antibodies is important for their function, and the contribution of such findings to stroke outcome is not yet clear. Notably, stroke induces immunodepression highlighted by a transient lymphopenia, lymphoid organ atrophy, and monocyte deactivation. While these effects might reduce the chances of autoreactivity, they increase the risk of infection in patients with stroke and most frequently in those with severe stroke. Therefore any potential brain protective effect of stroke-induced immunodepression by attenuating or preventing lymphocyte-mediated brain damage is confounded by stroke severity and an increased incidence of infections. Systemic inflammation due to a number of comorbidities that are frequent in patients with stroke is also associated to a poor outcome. Herein, we review some relevant findings regarding the identification of neural antigens in stroke and discuss their potential contribution to the functional outcome of stroke.
Topics: Animals; Antigen Presentation; Humans; Immune System; Stroke
PubMed: 27514673
DOI: 10.1007/s13311-016-0469-8