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Frontiers in Immunology 2022B cells have been long studied for their role and function in the humoral immune system. Apart from generating antibodies and an antibody-mediated memory response... (Review)
Review
B cells have been long studied for their role and function in the humoral immune system. Apart from generating antibodies and an antibody-mediated memory response against pathogens, B cells are also capable of generating cell-mediated immunity. It has been demonstrated by several groups that B cells can activate antigen-specific CD4 and CD8 T cells, and can have regulatory and cytotoxic effects. The function of B cells as professional antigen presenting cells (APCs) to activate T cells has been largely understudied. This, however, requires attention as several recent reports have demonstrated the importance of B cells within the tumor microenvironment, and B cells are increasingly being evaluated as cellular therapies. Antigen presentation through B cells can be through antigen-specific (B cell receptor (BCR) dependent) or antigen non-specific (BCR independent) mechanisms and can be modulated by a variety of intrinsic and external factors. This review will discuss the pathways and mechanisms by which B cells present antigens, and how B cells differ from other professional APCs.
Topics: Antigen Presentation; Antigen-Presenting Cells; B-Lymphocytes; CD8-Positive T-Lymphocytes; Receptors, Antigen, B-Cell
PubMed: 36159874
DOI: 10.3389/fimmu.2022.954936 -
Cellular & Molecular Immunology Aug 2020Immunometabolism plays a fundamental role in health and diseases and involves multiple genes and signals. Aconitate decarboxylase 1 (ACOD1; also known as IRG1) is... (Review)
Review
Immunometabolism plays a fundamental role in health and diseases and involves multiple genes and signals. Aconitate decarboxylase 1 (ACOD1; also known as IRG1) is emerging as a regulator of immunometabolism in inflammation and infection. Upregulation of ACOD1 expression occurs in activated immune cells (e.g., macrophages and monocytes) in response to pathogen infection (e.g., bacteria and viruses), pathogen-associated molecular pattern molecules (e.g., LPS), cytokines (e.g., TNF and IFNs), and damage-associated molecular patterns (e.g., monosodium urate). Mechanistically, several immune receptors (e.g., TLRs and IFNAR), adapter proteins (e.g., MYD88), ubiquitin ligases (e.g., A20), and transcription factors (e.g., NF-κB, IRFs, and STATs) form complex signal transduction networks to control ACOD1 expression in a context-dependent manner. Functionally, ACOD1 mediates itaconate production, oxidative stress, and antigen processing and plays dual roles in immunity and diseases. On the one hand, activation of the ACOD1 pathway may limit pathogen infection and promote embryo implantation. On the other hand, abnormal ACOD1 expression can lead to tumor progression, neurodegenerative disease, and immune paralysis. Further understanding of the function and regulation of ACOD1 is important for the application of ACOD1-based therapeutic strategies in disease.
Topics: Animals; Antigen Presentation; Carboxy-Lyases; Disease; Humans; Immune System; Immunity; Oxidative Stress
PubMed: 32601305
DOI: 10.1038/s41423-020-0489-5 -
Cell Research Jan 2017Immunotherapy using dendritic cell (DC)-based vaccination is an approved approach for harnessing the potential of a patient's own immune system to eliminate tumor cells... (Review)
Review
Immunotherapy using dendritic cell (DC)-based vaccination is an approved approach for harnessing the potential of a patient's own immune system to eliminate tumor cells in metastatic hormone-refractory cancer. Overall, although many DC vaccines have been tested in the clinic and proven to be immunogenic, and in some cases associated with clinical outcome, there remains no consensus on how to manufacture DC vaccines. In this review we will discuss what has been learned thus far about human DC biology from clinical studies, and how current approaches to apply DC vaccines in the clinic could be improved to enhance anti-tumor immunity.
Topics: Animals; Antigen Presentation; Antigens, Neoplasm; Dendritic Cells; Humans; Immunity; Immunotherapy; Vaccination
PubMed: 28025976
DOI: 10.1038/cr.2016.157 -
Nature Reviews. Immunology Sep 2022Blood vessel endothelial cells (ECs) have long been known to modulate inflammation by regulating immune cell trafficking, activation status and function. However,... (Review)
Review
Blood vessel endothelial cells (ECs) have long been known to modulate inflammation by regulating immune cell trafficking, activation status and function. However, whether the heterogeneous EC populations in various tissues and organs differ in their immunomodulatory capacity has received insufficient attention, certainly with regard to considering them for alternative immunotherapy. Recent single-cell studies have identified specific EC subtypes that express gene signatures indicative of phagocytosis or scavenging, antigen presentation and immune cell recruitment. Here we discuss emerging evidence suggesting a tissue-specific and vessel type-specific immunomodulatory role for distinct subtypes of ECs, here collectively referred to as 'immunomodulatory ECs' (IMECs). We propose that IMECs have more important functions in immunity than previously recognized, and suggest that these might be considered as targets for new immunotherapeutic approaches.
Topics: Antigen Presentation; Endothelial Cells; Humans; Immune System; Immunomodulation; Inflammation
PubMed: 35288707
DOI: 10.1038/s41577-022-00694-4 -
The Journal of Clinical Investigation Jan 2020Alterations in gut microbiota impact the pathophysiology of several diseases, including cancer. Radiotherapy (RT), an established curative and palliative cancer...
Alterations in gut microbiota impact the pathophysiology of several diseases, including cancer. Radiotherapy (RT), an established curative and palliative cancer treatment, exerts potent immune modulatory effects, inducing tumor-associated antigen (TAA) cross-priming with antitumor CD8+ T cell elicitation and abscopal effects. We tested whether the gut microbiota modulates antitumor immune response following RT distal to the gut. Vancomycin, an antibiotic that acts mainly on gram-positive bacteria and is restricted to the gut, potentiated the RT-induced antitumor immune response and tumor growth inhibition. This synergy was dependent on TAA cross presentation to cytolytic CD8+ T cells and on IFN-γ. Notably, butyrate, a metabolite produced by the vancomycin-depleted gut bacteria, abrogated the vancomycin effect. In conclusion, depletion of vancomycin-sensitive bacteria enhances the antitumor activity of RT, which has important clinical ramifications.
Topics: Animals; Antigen Presentation; Antigens, Neoplasm; Butyrates; CD8-Positive T-Lymphocytes; Dendritic Cells; Female; Gastrointestinal Microbiome; Mice; Mice, Knockout; Neoplasms, Experimental
PubMed: 31815742
DOI: 10.1172/JCI124332 -
Journal of Autoimmunity Nov 2015Both environmental and genetic triggers factor into the etiology of autoimmune thyroid disease (AITD), including Graves' disease (GD) and Hashimoto's thyroiditis (HT).... (Review)
Review
Both environmental and genetic triggers factor into the etiology of autoimmune thyroid disease (AITD), including Graves' disease (GD) and Hashimoto's thyroiditis (HT). Although the exact pathogenesis and causative interaction between environment and genes are unknown, GD and HT share similar immune-mediated mechanisms of disease. They both are characterized by the production of thyroid autoantibodies and by thyroidal lymphocytic infiltration, despite being clinically distinct entities with thyrotoxicosis in GD and hypothyroidism in HT. Family and population studies confirm the strong genetic influence and inheritability in the development of AITD. AITD susceptibility genes can be categorized as either thyroid specific (Tg, TSHR) or immune-modulating (FOXP3, CD25, CD40, CTLA-4, HLA), with HLA-DR3 carrying the highest risk. Of the AITD susceptibility genes, FOXP3 and CD25 play critical roles in the establishment of peripheral tolerance while CD40, CTLA-4, and the HLA genes are pivotal for T lymphocyte activation and antigen presentation. Polymorphisms in these immune-modulating genes, in particular, significantly contribute to the predisposition for GD, HT and, unsurprisingly, other autoimmune diseases. Emerging evidence suggests that single nucleotide polymorphisms (SNPs) in the immunoregulatory genes may functionally hinder the proper development of central and peripheral tolerance and alter T cell interactions with antigen presenting cells (APCs) in the immunological synapse. Thus, susceptibility genes for AITD contribute directly to the key mechanism underlying the development of organ-specific autoimmunity, namely the breakdown in self-tolerance. Here we review the major immune-modulating genes that are associated with AITD and their potential functional effects on thyroidal immune dysregulation.
Topics: Animals; Antigen Presentation; Autoimmune Diseases; Genetic Loci; Genetic Predisposition to Disease; Humans; Immune Tolerance; Immunogenetics; Phenotype; Thyroid Diseases
PubMed: 26235382
DOI: 10.1016/j.jaut.2015.07.009 -
Cellular & Molecular Immunology Jun 2020Dendritic cells are powerful antigen-presenting cells that are essential for the priming of T cell responses. In addition to providing T-cell-receptor ligands and... (Review)
Review
Dendritic cells are powerful antigen-presenting cells that are essential for the priming of T cell responses. In addition to providing T-cell-receptor ligands and co-stimulatory molecules for naive T cell activation and expansion, dendritic cells are thought to also provide signals for the differentiation of CD4+ T cells into effector T cell populations. The mechanisms by which dendritic cells are able to adapt and respond to the great variety of infectious stimuli they are confronted with, and prime an appropriate CD4+ T cell response, are only partly understood. It is known that in the steady-state dendritic cells are highly heterogenous both in phenotype and transcriptional profile, and that this variability is dependent on developmental lineage, maturation stage, and the tissue environment in which dendritic cells are located. Exposure to infectious agents interfaces with this pre-existing heterogeneity by providing ligands for pattern-recognition and toll-like receptors that are variably expressed on different dendritic cell subsets, and elicit production of cytokines and chemokines to support innate cell activation and drive T cell differentiation. Here we review current information on dendritic cell biology, their heterogeneity, and the properties of different dendritic cell subsets. We then consider the signals required for the development of different types of Th immune responses, and the cellular and molecular evidence implicating different subsets of dendritic cells in providing such signals. We outline how dendritic cell subsets tailor their response according to the infectious agent, and how such transcriptional plasticity enables them to drive different types of immune responses.
Topics: Animals; Antigen Presentation; Cell Differentiation; Dendritic Cells; Humans; Models, Biological; T-Lymphocytes, Helper-Inducer; Transcription, Genetic
PubMed: 32433540
DOI: 10.1038/s41423-020-0465-0 -
Cell Stem Cell May 2022Hematopoietic stem and progenitor cells (HSPCs) are responsible for the production of blood and immune cells. Throughout life, HSPCs acquire oncogenic aberrations that...
Hematopoietic stem and progenitor cells (HSPCs) are responsible for the production of blood and immune cells. Throughout life, HSPCs acquire oncogenic aberrations that can cause hematological cancers. Although molecular programs maintaining stem cell integrity have been identified, safety mechanisms eliminating malignant HSPCs from the stem cell pool remain poorly characterized. Here, we show that HSPCs constitutively present antigens via major histocompatibility complex class II. The presentation of immunogenic antigens, as occurring during malignant transformation, triggers bidirectional interactions between HSPCs and antigen-specific CD4 T cells, causing stem cell proliferation, differentiation, and specific exhaustion of aberrant HSPCs. This immunosurveillance mechanism effectively eliminates transformed HSPCs from the hematopoietic system, thereby preventing leukemia onset. Together, our data reveal a bidirectional interaction between HSPCs and CD4 T cells, demonstrating that HSPCs are not only passive receivers of immunological signals but also actively engage in adaptive immune responses to safeguard the integrity of the stem cell pool.
Topics: Antigen Presentation; Cell Differentiation; Hematopoietic Stem Cells; T-Lymphocytes
PubMed: 35523139
DOI: 10.1016/j.stem.2022.04.007 -
Seminars in Cell & Developmental Biology Dec 2018MR1 is a non-classical class I molecule that is highly conserved among mammals. Though discovered in 1995, only recently have MR1 ligands and antigens for MR1-restricted... (Review)
Review
MR1 is a non-classical class I molecule that is highly conserved among mammals. Though discovered in 1995, only recently have MR1 ligands and antigens for MR1-restricted T cells been described. Unlike the traditional class I molecules HLA-A, -B, and -C, little MR1 is on the cell surface. Rather, MR1 resides in discrete intracellular vesicles and the endoplasmic reticulum, and can present non-peptidic small molecules such as those found in the riboflavin biosynthesis pathway. Since mammals do not synthesize riboflavin, MR1 can serve as a sensor of the microbial metabolome and could be key to the early detection of intracellular infection. This review will summarize the current understanding of MR1-dependent antigen presentation.
Topics: Animals; Antigen Presentation; Cell Membrane; Histocompatibility Antigens Class I; Humans; Ligands; Minor Histocompatibility Antigens; T-Lymphocytes
PubMed: 30449535
DOI: 10.1016/j.semcdb.2017.11.028 -
Activated SUMOylation restricts MHC class I antigen presentation to confer immune evasion in cancer.The Journal of Clinical Investigation May 2022Activated SUMOylation is a hallmark of cancer. Starting from a targeted screening for SUMO-regulated immune evasion mechanisms, we identified an evolutionarily conserved...
Activated SUMOylation is a hallmark of cancer. Starting from a targeted screening for SUMO-regulated immune evasion mechanisms, we identified an evolutionarily conserved function of activated SUMOylation, which attenuated the immunogenicity of tumor cells. Activated SUMOylation allowed cancer cells to evade CD8+ T cell-mediated immunosurveillance by suppressing the MHC class I (MHC-I) antigen-processing and presentation machinery (APM). Loss of the MHC-I APM is a frequent cause of resistance to cancer immunotherapies, and the pharmacological inhibition of SUMOylation (SUMOi) resulted in reduced activity of the transcriptional repressor scaffold attachment factor B (SAFB) and induction of the MHC-I APM. Consequently, SUMOi enhanced the presentation of antigens and the susceptibility of tumor cells to CD8+ T cell-mediated killing. Importantly, SUMOi also triggered the activation of CD8+ T cells and thereby drove a feed-forward loop amplifying the specific antitumor immune response. In summary, we showed that activated SUMOylation allowed tumor cells to evade antitumor immunosurveillance, and we have expanded the understanding of SUMOi as a rational therapeutic strategy for enhancing the efficacy of cancer immunotherapies.
Topics: Antigen Presentation; Histocompatibility Antigens Class I; Humans; Immune Evasion; Neoplasms; Sumoylation
PubMed: 35499080
DOI: 10.1172/JCI152383