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Cell Systems Jul 2020Computational prediction of the peptides presented on major histocompatibility complex (MHC) class I proteins is an important tool for studying T cell immunity. The...
Computational prediction of the peptides presented on major histocompatibility complex (MHC) class I proteins is an important tool for studying T cell immunity. The data available to develop such predictors have expanded with the use of mass spectrometry to identify naturally presented MHC ligands. In addition to elucidating binding motifs, the identified ligands also reflect the antigen processing steps that occur prior to MHC binding. Here, we developed an integrated predictor of MHC class I presentation that combines new models for MHC class I binding and antigen processing. Considering only peptides first predicted by the binding model to bind strongly to MHC, the antigen processing model is trained to discriminate published mass spectrometry-identified MHC class I ligands from unobserved peptides. The integrated model outperformed the two individual components as well as NetMHCpan 4.0 and MixMHCpred 2.0.2 on held-out mass spectrometry experiments. Our predictors are implemented in the open source MHCflurry package, version 2.0 (github.com/openvax/mhcflurry).
Topics: Alleles; Antigen Presentation; Histocompatibility Antigens Class I; Humans; Peptides
PubMed: 32711842
DOI: 10.1016/j.cels.2020.06.010 -
Cellular & Molecular Immunology Jan 2021The liver is an important immunological organ that controls systemic tolerance. The liver harbors professional and unconventional antigen-presenting cells that are... (Review)
Review
The liver is an important immunological organ that controls systemic tolerance. The liver harbors professional and unconventional antigen-presenting cells that are crucial for tolerance induction and maintenance. Orchestrating the immune response in homeostasis depends on a healthy and well-toned immunological liver microenvironment, which is maintained by the crosstalk of liver-resident antigen-presenting cells and intrahepatic and liver-infiltrating leukocytes. In response to pathogens or autoantigens, tolerance is disrupted by unknown mechanisms. Intrahepatic parenchymal and nonparenchymal cells exhibit unique antigen-presenting properties. The presentation of microbial and endogenous lipid-, metabolite- and peptide-derived antigens from the gut via conventional and nonconventional mechanisms can educate intrahepatic immune cells and elicit effector responses or tolerance. Perturbation of this balance results in autoimmune liver diseases, such as autoimmune hepatitis, primary biliary cholangitis, and primary sclerosing cholangitis. Although the exact etiologies of these autoimmune liver diseases are unknown, it is thought that the disruption of tolerance towards self-antigens and microbial metabolites and lipids, as well as alterations in bile acid composition, may result in changes in effector cell activation and polarization and may reduce or impair protective anti-inflammatory regulatory T and B cell responses. Additionally, the canonical and noncanonical transmission of antigens and antigen:MHC complexes via trogocytosis or extracellular vesicles between different (non) immune cells in the liver may play a role in the induction of hepatic inflammation and tolerance. Here, we summarize emerging aspects of antigen presentation, autoantibody production, and the application of novel therapeutic approaches in the characterization and treatment of autoimmune liver diseases.
Topics: Animals; Antigen Presentation; Antigen-Presenting Cells; Autoantibodies; Autoimmune Diseases; Humans; Immune Tolerance; Liver Diseases; T-Lymphocytes, Regulatory
PubMed: 33110250
DOI: 10.1038/s41423-020-00568-6 -
Oncotarget Aug 2015
Topics: Antigen Presentation; Cross Reactions; Humans; Membrane Proteins; SEC Translocation Channels
PubMed: 26348326
DOI: 10.18632/oncotarget.4587 -
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 -
Biochemical Society Transactions Apr 2022Evading immune destruction is one of the hallmarks of cancer. A key mechanism of immune evasion deployed by tumour cells is to reduce neoantigen presentation through... (Review)
Review
Evading immune destruction is one of the hallmarks of cancer. A key mechanism of immune evasion deployed by tumour cells is to reduce neoantigen presentation through down-regulation of the antigen presentation machinery. MHC-I and MHC-II proteins are key components of the antigen presentation machinery responsible for neoantigen presentation to CD8+ and CD4+ T lymphocytes, respectively. Their expression in tumour cells is modulated by a complex interplay of genomic, transcriptomic and post translational factors involving multiple intracellular antigen processing pathways. Ongoing research investigates mechanisms invoked by cancer cells to abrogate MHC-I expression and attenuate anti-tumour CD8+ cytotoxic T cell response. The discovery of MHC-II on tumour cells has been less characterized. However, this finding has triggered further interest in utilising tumour-specific MHC-II to harness sustained anti-tumour immunity through the activation of CD4+ T helper cells. Tumour-specific expression of MHC-I and MHC-II has been associated with improved patient survival in most clinical studies. Thus, their reactivation represents an attractive way to unleash anti-tumour immunity. This review provides a comprehensive overview of physiologically conserved or novel mechanisms utilised by tumour cells to reduce MHC-I or MHC-II expression. It outlines current approaches employed at the preclinical and clinical trial interface towards reversing these processes in order to improve response to immunotherapy and survival outcomes for patients with cancer.
Topics: Antigen Presentation; CD4-Positive T-Lymphocytes; Humans; Immunologic Surveillance; Immunotherapy; Neoplasms
PubMed: 35343573
DOI: 10.1042/BST20210961 -
Molecular Carcinogenesis Feb 2022Presentation of tumor antigens is a critical step in producing a robust antitumor immune response. Classically tumor antigens are thought to be presented to both CD8 and... (Review)
Review
Presentation of tumor antigens is a critical step in producing a robust antitumor immune response. Classically tumor antigens are thought to be presented to both CD8 and CD4 T cells by professional antigen-presenting cells (pAPCs) like dendritic cells using major histocompatibility complexes (MHC) I and II. But recent evidence suggests that in the tumor microenvironment (TME) cells other than pAPCs are capable of presenting tumor antigens on both MHC I and II. The evidence currently available on tumor antigen presentation by epithelial cells, vascular endothelial cells (VECs), fibroblasts, and cancer cells is reviewed herein. We refer to these cell types in the TME as "amateur" APCs (aAPCs). These aAPCs greatly outnumber pAPCs in the TME and could, potentially, play a significant role in priming an antitumor immune response. This new evidence supports a different perspective on antigen presentation and suggests new approaches that can be taken in designing immunotherapies to increase T cell priming.
Topics: Antigen Presentation; Antigen-Presenting Cells; Antigens, Neoplasm; Dendritic Cells; Endothelial Cells; Humans; Tumor Microenvironment
PubMed: 34570920
DOI: 10.1002/mc.23354 -
Ocular Immunology and Inflammation Aug 2016HLA-B27 associated disorders comprise a group of inflammatory conditions which have in common an association with the HLA class I molecule, HLA-B27. Given this... (Review)
Review
HLA-B27 associated disorders comprise a group of inflammatory conditions which have in common an association with the HLA class I molecule, HLA-B27. Given this association, these diseases are classically considered disorders of adaptive immunity. However, mounting data are challenging this assumption and confirming that innate immunity plays a more prominent role in pathogenesis than previously suspected. In this review, the concept of autoinflammation is discussed and evidence is presented from human and animal models to support a key role for innate immunity in HLA-B27 associated disorders.
Topics: Antigen Presentation; HLA-B27 Antigen; Humans; Immunity, Innate; Spondylarthritis; Uveitis, Anterior
PubMed: 27229619
DOI: 10.1080/09273948.2016.1175641 -
Immunology Letters Jul 2022Neutrophils are the most abundant cells of the immune system and key in combating infections through phagocytosis, reactive oxygen species, neutrophil extracellular...
Neutrophils are the most abundant cells of the immune system and key in combating infections through phagocytosis, reactive oxygen species, neutrophil extracellular traps, and secretion of cytokines and antimicrobial peptides. Beyond this, they may influence the adaptive immune response by modulating CD4 T cell responses. In response to cytokines, mainly GM-CSF, but also IFN-γ and TNF-α, neutrophils express major histocompatibility complex class II molecules on their surface. However, to function as antigen-presenting cells for CD4 T cells, more requirements need to be fulfilled, like antigen internalization, processing into fragments containing T cell epitopes, and their presentation on the cell surface together with costimulatory molecules. Here, studies investigating the key features of antigen-presentation by neutrophils are summarized and discussed. Together, they provide evidence for a potential of neutrophils to specifically activate antigen-experienced CD4 T cells.
Topics: Antigen Presentation; Antigen-Presenting Cells; CD4-Positive T-Lymphocytes; Cytokines; Histocompatibility Antigens Class II; Neutrophils
PubMed: 35577002
DOI: 10.1016/j.imlet.2022.04.007 -
Microbiology Spectrum Jun 2016Unlike B cells, CD8-positive and CD4-positive T cells of the adaptive immune system do not recognize intact foreign proteins but instead recognize polypeptide fragments... (Review)
Review
Unlike B cells, CD8-positive and CD4-positive T cells of the adaptive immune system do not recognize intact foreign proteins but instead recognize polypeptide fragments of potential antigens. These antigenic peptides are expressed on the surface of antigen presenting cells bound to MHC class I and MHC class II proteins. Here, we review the basics of antigen acquisition by antigen presenting cells, antigen proteolysis into polypeptide fragments, antigenic peptide binding to MHC proteins, and surface display of both MHC class I-peptide and MHC class II-peptide complexes.
Topics: Animals; Antigen Presentation; Humans; Myeloid Cells
PubMed: 27337472
DOI: 10.1128/microbiolspec.MCHD-0008-2015 -
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