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Current Opinion in Immunology Aug 2023After two decades of the study of lipid antigens that activate CD1-restricted T cells, new studies show how autoreactive αβ T-cell receptors (TCRs) can directly... (Review)
Review
After two decades of the study of lipid antigens that activate CD1-restricted T cells, new studies show how autoreactive αβ T-cell receptors (TCRs) can directly recognize the outer surface of CD1 proteins in ways that are lipid-agnostic. Most recently, this lipid agnosticism has turned to negativity, with the discovery of natural CD1 ligands that dominantly negatively block autoreactive αβ TCR binding to CD1a and CD1d. This review highlights the basic differences between positive and negative regulation of cellular systems. We outline strategies to discover lipid inhibitors of CD1-reactive T cells, whose roles in vivo are becoming clear, especially in CD1-mediated skin disease.
Topics: Humans; Antigen Presentation; T-Lymphocytes; Receptors, Antigen, T-Cell; Antigens; Lipids; Antigens, CD1
PubMed: 37245411
DOI: 10.1016/j.coi.2023.102339 -
Clinical Gastroenterology and... Jul 2023A functional cure of chronic hepatitis B defined as sustained hepatitis B surface antigen loss after finite course of therapy is rarely achieved with current therapy but... (Review)
Review
A functional cure of chronic hepatitis B defined as sustained hepatitis B surface antigen loss after finite course of therapy is rarely achieved with current therapy but is the goal of novel treatments. Understanding the virological and immunological mechanisms of hepatitis B virus persistence has enabled the identification of novel treatment targets, drug discovery, and the evaluation of novel agents in clinical trials. Lessons were learned from early phase 1 and phase 2 trials regarding the antiviral activity and safety profile of these agents. There is a strong rationale to combine agents to reduce viral replication, reduce viral antigen load, invigorate immune responses, and induce specific adaptive immune responses. Nucleos(t)ide analogs will likely remain an essential backbone of future combinations to control viral replication and prevent resistance to antiviral drugs. In this review, we discuss perspectives on approaches to achieving functional cure, with a review of virological and immunological strategies, highlighting challenges and unresolved questions with the various attempts to achieve cure, as well as exploring alternative endpoints such as partial cure and new noninvasive viral and immunological biomarkers to stratify patients and predict/monitor antiviral response.
Topics: Humans; Hepatitis B, Chronic; Hepatitis B virus; Hepatitis B Surface Antigens; Antiviral Agents; Virus Replication; DNA, Viral; Hepatitis B
PubMed: 37080262
DOI: 10.1016/j.cgh.2023.02.032 -
Current Opinion in Organ Transplantation Oct 2023De novo HLA-DQ antibodies are the most frequently observed after solid-organ allotransplantation; and are associated with the worse adverse graft outcomes compared with... (Review)
Review
PURPOSE OF REVIEW
De novo HLA-DQ antibodies are the most frequently observed after solid-organ allotransplantation; and are associated with the worse adverse graft outcomes compared with all other HLA antibodies. However, the biological explanation for this observation is not yet known. Herein, we examine unique characteristics of alloimmunity directed specifically against HLA-DQ molecules.
RECENT FINDINGS
While investigators attempted to decipher functional properties of HLA class II antigens that may explain their immunogenicity and pathogenicity, most early studies focused on the more expressed molecule - HLA-DR. We here summarize up-to-date literature documenting specific features of HLA-DQ, as compared to other class II HLA antigens. Structural and cell-surface expression differences have been noted on various cell types. Some evidence suggests variations in antigen-presenting function and intracellular activation pathways after antigen/antibody interaction.
SUMMARY
The clinical effects of donor-recipient incompatibility at HLA-DQ, the risk of generating de novo antibodies leading to rejection, and the inferior graft outcomes indicate increased immunogenicity and pathogenicity that is unique to this HLA antigen. Clearly, knowledge generated for HLA-DR cannot be applied interchangeably. Deeper understanding of features unique to HLA-DQ may support the generation of targeted preventive-therapeutic strategies and ultimately improve solid-organ transplant outcomes.
Topics: Humans; Kidney Transplantation; Isoantibodies; HLA-DQ Antigens; Histocompatibility Testing; HLA-DR Antigens; Graft Rejection
PubMed: 37219535
DOI: 10.1097/MOT.0000000000001079 -
Current Opinion in Immunology Oct 2023Major histocompatibility complex class I (MHC class I) molecules facilitate subcellular immune surveillance by presenting peptides on the cell surface. MHC class I... (Review)
Review
Major histocompatibility complex class I (MHC class I) molecules facilitate subcellular immune surveillance by presenting peptides on the cell surface. MHC class I assembly with peptides generally happens in the endoplasmic reticulum (ER). Peptides are processed in the cytosol, transported into the ER, and assembled with MHC class I heavy and light chains. However, as many pathogens reside within multiple subcellular organelles, peptide sampling across non-cytosolic compartments is also important. MHC class I molecules internalize from the cell surface into endosomes and constitutively traffic between endosomes and the cell surface. Within endosomes, MHC class I molecules assemble with both exogenous and endogenous antigens processed within these compartments. Human MHC classI polymorphisms, well known to affect ER assembly modes, also influence endosomal assembly outcomes, an area of current interest to the field.
Topics: Humans; Histocompatibility Antigens Class I; HLA Antigens; Peptides; Endosomes; Major Histocompatibility Complex; Histocompatibility Antigens Class II
PubMed: 37379719
DOI: 10.1016/j.coi.2023.102356 -
Trends in Immunology Sep 2023CD8 cytotoxic T lymphocytes (CTLs) play a crucial role in targeting virus-infected and cancer cells. Although other cytotoxic lymphocytes such as CD4 T and natural... (Review)
Review
CD8 cytotoxic T lymphocytes (CTLs) play a crucial role in targeting virus-infected and cancer cells. Although other cytotoxic lymphocytes such as CD4 T and natural killer (NK) cells, as well as chimeric antigen receptor (CAR)-T cells, can also identify and destroy aberrant cells, they seem to be significantly less potent based on available experimental data. Here, I contemplate the molecular mechanisms controlling the sensitivity and kinetics of granule-mediated CD8 T cell cytolytic responses. I posit that the clustering of MHC-I molecules and T cell receptors (TCRs) on the cell surface, as well as the contribution of the CD8 co-receptor, are major factors driving exceptionally potent cytolytic responses. I also contend that CD8 T cells with known specificity and engineered TCR-T cells might be among the most efficient cytolytic effectors for treating patients suffering from viral infections or cancer.
Topics: Humans; CD8-Positive T-Lymphocytes; T-Lymphocytes, Cytotoxic; Receptors, Antigen, T-Cell; CD8 Antigens; Killer Cells, Natural
PubMed: 37558570
DOI: 10.1016/j.it.2023.07.005 -
Liver International : Official Journal... Sep 2023Hepatitis B virus (HBV) infection is a major cause of hepatocellular carcinoma (HCC) development and progression. The aim of this study was to mechanistically...
BACKGROUND AND AIMS
Hepatitis B virus (HBV) infection is a major cause of hepatocellular carcinoma (HCC) development and progression. The aim of this study was to mechanistically investigate the involvement of Hippo signalling in HBV surface antigen (HBsAg)-dependent neoplastic transformation.
METHODS
Liver tissue and hepatocytes from HBsAg-transgenic mice were examined for the Hippo cascade and proliferative events. Functional experiments in mouse hepatoma cells included knockdown, overexpression, luciferase reporter assays and chromatin immunoprecipitation. Results were validated in HBV-related HCC biopsies.
RESULTS
Hepatic expression signatures in HBsAg-transgenic mice correlated with YAP responses, cell cycle control, DNA damage and spindle events. Polyploidy and aneuploidy occurred in HBsAg-transgenic hepatocytes. Suppression and inactivation of MST1/2 led to the loss of YAP phosphorylation and the induction of BMI1 expression in vivo and in vitro. Increased BMI1 directly mediated cell proliferation associated with decreased level of p16 , p19 , p53 and Caspase 3 as well as increased Cyclin D1 and γ-H2AX expression. Chromatin immunoprecipitation and the analysis of mutated binding sites in dual-luciferase reporter assays confirmed that the YAP/TEAD4 transcription factor complex bound and activated the Bmi1 promoter. In chronic hepatitis B patients, paired liver biopsies of non-tumour and tumour tissue indicated a correlation between YAP expression and the abundance of BMI1. In a proof-of-concept, treatment of HBsAg-transgenic mice with YAP inhibitor verteporfin directly suppressed the BMI1-related cell cycle.
CONCLUSION
HBV-associated proliferative HCC might be related to the HBsAg-YAP-BMI1 axis and offer a potential target for the development of new therapeutic approaches.
Topics: Animals; Mice; Carcinoma, Hepatocellular; Hepatitis B; Hepatitis B Surface Antigens; Hepatitis B virus; Liver Neoplasms; Mice, Transgenic
PubMed: 37312627
DOI: 10.1111/liv.15628 -
Molecular Immunology Jun 2024CD1 molecules are well known for their role in binding and presenting lipid antigens to mediate the activation of CD1-restricted T cells. However, much less appreciated... (Review)
Review
CD1 molecules are well known for their role in binding and presenting lipid antigens to mediate the activation of CD1-restricted T cells. However, much less appreciated is the fact that CD1 molecules can have additional "unconventional" roles which impact the activation and functions of CD1-expressing cells, ultimately controlling tissue homeostasis as well as the progression of inflammatory and infectious diseases. Some of these roles are mediated by so-called reverse signalling, by which crosslinking of CD1 molecules at the cell surface initiates intracellular signalling. On the other hand, CD1 molecules can also control metabolic and inflammatory pathways in CD1-expressing cells through cell-intrinsic mechanisms independent of CD1 ligation. Here, we review the evidence for "unconventional" functions of CD1 molecules and the outcomes of such roles for health and disease.
Topics: Animals; Humans; Antigen Presentation; Antigens, CD1; Inflammation; Lymphocyte Activation; Signal Transduction; T-Lymphocytes
PubMed: 38579449
DOI: 10.1016/j.molimm.2024.03.011 -
Molecular Nutrition & Food Research May 2024Alpha-gal syndrome (AGS) is a mammalian meat allergy associated with tick bites and specific IgE to the oligosaccharide galactose-α-1,3-galactose (α-gal). Recent...
Alpha-gal syndrome (AGS) is a mammalian meat allergy associated with tick bites and specific IgE to the oligosaccharide galactose-α-1,3-galactose (α-gal). Recent studies have shown that 10-20% of AGS patients also react to the dairy proteins. Considering the already described role of the meat lipid fraction in AGS manifestations, the aim of this work has been to investigate whether the milk fat globule proteins (MFGPs) could be involved in AGS. The MFGPs are extracted and their recognition by the IgE of AGS patients is proved through immunoblotting experiments. The identification of the immunoreactive proteins by LC-HRMS analysis allows to demonstrate for the first time that butyrophillin, lactadherin, and xanthine oxidase (XO) are α-gal glycosylated. The role of xanthine oxidase seems to be prevalent since it is highly recognized by both the anti-α-gal antibody and AGS patient sera. The results obtained in this study provide novel insights in the characterization of α-Gal carrying glycoproteins in bovine milk, supporting the possibility that milk, especially in its whole form, may give reactions in AGS patients. Although additional factors are probably associated with the clinical manifestations, the avoidance of milk and milk products should be considered in individuals with AGS showing symptoms related to milk consumption.
Topics: Glycoproteins; Humans; Animals; Lipid Droplets; Glycolipids; Cattle; Milk; Allergens; Butyrophilins; Female; Milk Proteins; Immunoglobulin E; Food Hypersensitivity; Tick Bites; Adult; Male; Antigens, Surface; Middle Aged; alpha-Galactosidase; Disaccharides
PubMed: 38704747
DOI: 10.1002/mnfr.202300796 -
Frontiers in Immunology 2023Trophoblast cell surface antigen 2 (Trop2) exhibits limited expression in normal tissues but is over-expressed across various solid tumors. The effectiveness of... (Review)
Review
Trophoblast cell surface antigen 2 (Trop2) exhibits limited expression in normal tissues but is over-expressed across various solid tumors. The effectiveness of anti-Trop2 antibody-drug conjugate (ADC) in managing breast cancer validates Trop2 as a promising therapeutic target for cancer treatment. However, excessive toxicity and a low response rate of ADCs pose ongoing challenges. Safer and more effective strategies should be developed for Trop2-positive cancers. The dynamic structural attributes and the oligomeric assembly of Trop2 present formidable obstacles to the progression of innovative targeted therapeutics. In this review, we summarize recent advancements in understanding Trop2's structure and provide an overview of the epitope characteristics of Trop2-targeted agents. Furthermore, we discuss the correlation between anti-Trop2 agents' epitopes and their respective functions, particularly emphasizing their efficacy and specificity in targeted therapies.
Topics: Humans; Antigens, Neoplasm; Cell Adhesion Molecules; Neoplasms; Immunoconjugates
PubMed: 38179054
DOI: 10.3389/fimmu.2023.1332489 -
Current Opinion in Immunology Aug 2023Viral blockade of the transporter associated with antigen processing (TAP) diminishes surface and endosomal recycling compartment levels of major histocompatibility... (Review)
Review
Viral blockade of the transporter associated with antigen processing (TAP) diminishes surface and endosomal recycling compartment levels of major histocompatibility complex class-I (MHC-I) in dendritic cells (DCs), and compromises both classical MHC-I presentation and canonical cross-presentation during infection to impair CD8 T-cell immunity. Virus-specific CD8 T cells are thought to be cross-primed mostly by uninfected TAP-sufficient DCs through cross-presentation of viral peptides from internalized virus-infected dying cells. The dilemma is that CD8 T cells primed to TAP-dependent viral peptides are mismatched to the TAP-independent epitopes presented on tissues infected with immune-evasive viruses. Noncanonical cross-presentation in DCs overcomes cell-intrinsic TAP blockade to nevertheless prime protective TAP-independent CD8 T cells best-matched against the infection. Exploitation of noncanonical cross-presentation may prevent chronic infections with immune-evasive viruses. It may also control immune-evasive cancers that have downmodulated TAP expression.
Topics: Humans; Cross-Priming; Dendritic Cells; Antigen Presentation; Histocompatibility Antigens Class I; CD8-Positive T-Lymphocytes; Membrane Transport Proteins; Peptides; Viruses
PubMed: 37116384
DOI: 10.1016/j.coi.2023.102327