scholarly journals Invariant chain regulates endosomal fusion and maturation through the SNARE Vti1b

2019 ◽  
Author(s):  
Dominik Frei ◽  
Azzurra Margiotta ◽  
Marita Borg Distefano ◽  
Mohamed Moulefera ◽  
Lennert Janssen ◽  
...  
Keyword(s):  
Antigen Processing ◽  
Snare Proteins ◽  
Invariant Chain ◽  
Endosomal Trafficking ◽  
Cellular Functions ◽  
Rnai Silencing ◽  
Adaptive Immune ◽  
Endosomal Pathway ◽  
Antigen Presenting

AbstractInvariant chain (Ii) is an important multifunctional player in the regulation of adaptive immune responses and is responsible for several cellular functions related to MHCI and MHCII antigen loading and antigen presentation. While regulating endosomal trafficking of MHCII and other proteins that bind to Ii, this molecule is able to influence the endosomal pathway delaying the maturation of endosomes to the late endosomal loading compartments. When expressed in cells Ii is found to increase endosomal size, but the mechanisms for this is not known. We used RNAi silencing to identify SNARE proteins controlling Ii induced increase of endosomal size and delay of the endosomal pathway. Ii was found to interact with the SNARE protein Vti1b. Vti1b localized at the contact sites of fusing Ii positive endosomes and a tailless Ii was able to relocate Vti1b to the plasma membrane. Furthermore, silencing Vti1b, abrogated the delay in endosomal maturation induced by Ii expression. In conclusion, Ii interacts with Vti1b and this interaction is fundamental for Ii-mediated alteration of the endosomal pathway. We propose that Ii, by interacting with SNAREs, in particular Vti1B in the biosynthetic pathway of antigen presenting cells, is able to assemble SNARE directed fusion partners in the early part of the endosomal pathway that lead to a slower endosomal maturation for efficient antigen processing and antigen loading.

scholarly journals Invariant chain regulates endosomal fusion and maturation through an interaction with the SNARE Vti1b

2020 ◽  
Vol 133 (19) ◽  
pp. jcs244624
Author(s):  
Azzurra Margiotta ◽  
Dominik M. Frei ◽  
Ingrid Hegnes Sendstad ◽  
Lennert Janssen ◽  
Jacques Neefjes ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Antigen Processing ◽  
Molecular Mechanisms ◽  
Antigen Presenting Cells ◽  
Invariant Chain ◽  
Histocompatibility Complex ◽  
Speed Up ◽  
Endosomal Pathway ◽  
Antigen Presenting

ABSTRACTThe invariant chain (Ii, also known as CD74) is a multifunctional regulator of adaptive immune responses and is responsible for sorting major histocompatibility complex class I and class II (MHCI and MHCII, respectively) molecules, as well as other Ii-associated molecules, to a specific endosomal pathway. When Ii is expressed, endosomal maturation and proteolytic degradation of proteins are delayed and, in non-antigen presenting cells, the endosomal size increases, but the molecular mechanisms underlying this are not known. We identified that a SNARE, Vti1b, is essential for regulating these Ii-induced effects. Vti1b binds to Ii and is localized at the contact sites of fusing Ii-positive endosomes. Furthermore, truncated Ii lacking the cytoplasmic tail, which is not internalized from the plasma membrane, relocates Vti1b to the plasma membrane. Knockout of Ii in an antigen-presenting cell line was found to speed up endosomal maturation, whereas silencing of Vti1b inhibits the Ii-induced maturation delay. Our results suggest that Ii, by interacting with the SNARE Vti1b in antigen-presenting cells, directs specific Ii-associated SNARE-mediated fusion in the early part of the endosomal pathway that leads to a slower endosomal maturation for efficient antigen processing and MHC antigen loading.

Glutathione and glutathione derivatives in immunotherapy

2017 ◽  
Vol 398 (2) ◽  
pp. 261-275 ◽  
Author(s):  
Alessandra Fraternale ◽  
Serena Brundu ◽  
Mauro Magnani
Keyword(s):  
Immune Response ◽  
Antigen Processing ◽  
Viral Infections ◽  
De Novo ◽  
Cellular Functions ◽  
Animal Cells ◽  
Cellular Environment ◽  
Th2 Immune Response ◽  
Wide Range ◽  
Antigen Presenting

Abstract Reduced glutathione (GSH) is the most prevalent non-protein thiol in animal cells. Its de novo and salvage synthesis serves to maintain a reduced cellular environment, which is important for several cellular functions. Altered intracellular GSH levels are observed in a wide range of pathologies, including several viral infections, as well as in aging, all of which are also characterized by an unbalanced Th1/Th2 immune response. A central role in influencing the immune response has been ascribed to GSH. Specifically, GSH depletion in antigen-presenting cells (APCs) correlates with altered antigen processing and reduced secretion of Th1 cytokines. Conversely, an increase in intracellular GSH content stimulates IL-12 and/or IL-27, which in turn induces differentiation of naive CD4+ T cells to Th1 cells. In addition, GSH has been shown to inhibit the replication/survival of several pathogens, i.e. viruses and bacteria. Hence, molecules able to increase GSH levels have been proposed as new tools to more effectively hinder different pathogens by acting as both immunomodulators and antimicrobials. Herein, the new role of GSH and its derivatives as immunotherapeutics will be discussed.

scholarly journals A novel antigen-processing-defective phenotype in major histocompatibility complex class II-positive CIITA transfectants is corrected by interferon-gamma.

1995 ◽  
Vol 182 (6) ◽  
pp. 1793-1799 ◽  
Author(s):  
C A Siegrist ◽  
E Martinez-Soria ◽  
I Kern ◽  
B Mach
Keyword(s):  
Major Histocompatibility Complex ◽  
Mhc Class Ii ◽  
Interferon Gamma ◽  
Antigen Processing ◽  
Antigen Presenting Cells ◽  
Class Ii ◽  
Invariant Chain ◽  
Major Histocompatibility ◽  
Histocompatibility Complex ◽  
Antigen Presenting

Presentation of exogenous protein antigens to T lymphocytes is based on the intersection of two complex pathways: (a) synthesis, assembly, and transport of major histocompatibility complex (MHC) class II-invariant chain complexes from the endoplasmic reticulum to a specialized endosomal compartment, and (b) endocytosis, denaturation, and proteolysis of antigens followed by loading of antigenic peptides onto newly synthesized MHC class II molecules. It is believed that expression of MHC class II heterodimers, invariant chain and human leukocyte antigen-DM is both necessary and sufficient to reconstitute a functional MHC class II loading compartment in antigen-presenting cells. Expression of each of these essential molecules is under the control of the MHC class II transactivator CIITA. Unexpectedly, however, whereas interferon gamma stimulation does confer effective antigen-processing function to nonprofessional antigen presenting cells, such as melanoma cells, expression of the CIITA transactivator alone is not sufficient. Activation of antigen-specific T cells thus requires additional CIITA-independent factor(s), and such factor(s) can be induced by interferon gamma.

scholarly journals Predominant HLA-class II bound self-peptides of a hematopoietic progenitor cell line are derived from intracellular proteins

Blood ◽  
1996 ◽  
Vol 87 (12) ◽  
pp. 5104-5112 ◽  
Author(s):  
PE Harris ◽  
A Maffei ◽  
AI Colovai ◽  
J Kinne ◽  
S Tugulea ◽  
...  
Keyword(s):  
Progenitor Cells ◽  
Mhc Class Ii ◽  
Antigen Processing ◽  
Antigen Presenting Cells ◽  
Class Ii ◽  
Hla Class Ii ◽  
Invariant Chain ◽  
Hla Dr ◽  
Antigen Presenting ◽  
Self Peptides

Human myeloid progenitor cells temporarily express HLA class II molecules during the differentiation pathway to granulocytes and macrophages. The significance of major histocompatibility complex (MHC) class II molecules at this stage of development is unknown. As a first stop of inquiry into their function, we have characterized the profile of major self-peptides bound to the HLA-DR molecules expressed by KG-1 cells, a line that shares many of the phenotypic characteristics of colony-forming unit-granulocyte-macrophage progenitors. Searches of protein data bases showed that all matching peptides bound to the HLA- DR molecules of KG-1 cells corresponded to intracellular, rather than exogenous or transmembrane, precursor proteins. Because the absence of a conventional self-peptide repertoire could be related to altered trafficking of class II molecules, the biosynthesis of HLA-DR and the invariant chain proteins was determined. The MHC class II associated invariant chain protein is synthesized normally in KG-1 cells, but processed fragments of invariant chain, class II-associated invariant chain peptides (CLIPs), occupy the antigen-binding groove of KG-1 class II molecules at a much lower frequency compared with that of mature antigen-presenting cells. Low CLIP occupancy of HLA-DR is a characteristic shared by KG-1 cells, normal CD34+ progenitor cells, and HLA-DR+ breast carcinoma cells. The unusual profile of MHC class II bound peptides and the low level of CLIP bound to HLA-DR suggest that the antigen-processing pathway of KG-1 is different from that characterized in professional antigen-presenting cells and that exogenous antigen-processing may be a developmentally acquired characteristic in the myeloid lineage.

scholarly journals MRGPR-mediated activation of local mast cells clears cutaneous bacterial infection and protects against reinfection

2019 ◽  
Vol 5 (1) ◽  
pp. eaav0216 ◽  
Author(s):  
Mohammad Arifuzzaman ◽  
Yuvon R. Mobley ◽  
Hae Woong Choi ◽  
Pradeep Bist ◽  
Cristina A. Salinas ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Wound Healing ◽  
Dendritic Cells ◽  
Mast Cells ◽  
Connective Tissue ◽  
Selective Activation ◽  
Adaptive Immune ◽  
Antigen Presenting ◽  
G Protein Coupled ◽  
Draining Lymph Nodes

Mast cells (MCs) are strategically distributed at barrier sites and prestore various immunocyte-recruiting cytokines, making them ideal targets for selective activation to treat peripheral infections. Here, we report that topical treatment with mastoparan, a peptide MC activator (MCA), enhances clearance ofStaphylococcus aureusfrom infected mouse skins and accelerates healing of dermonecrotic lesions. Mastoparan functions by activating connective tissue MCs (CTMCs) via the MRGPRX2 (Mas-related G protein-coupled receptor member X2) receptor. Peripheral CTMC activation, in turn, enhances recruitment of bacteria-clearing neutrophils and wound-healing CD301b+dendritic cells. Consistent with MCs playing a master coordinating role, MC activation also augmented migration of various antigen-presenting dendritic cells to draining lymph nodes, leading to stronger protection against a second infection challenge. MCAs therefore orchestrate both the innate and adaptive immune arms, which could potentially be applied to combat peripheral infections by a broad range of pathogens.

Cellular side of acquired immunity (B cells)

2013 ◽  
pp. 371-378
Author(s):  
Thomas Dörner ◽  
Peter E. Lipsky
Keyword(s):  
B Cells ◽  
B Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Plasma Cells ◽  
Adaptive Immune System ◽  
Adaptive Immune ◽  
B Cell Homeostasis ◽  
Anti Cd20 ◽  
Antigen Presenting

B cells have gained interest in rheumatoid arthritis (RA) beyond being the precursors of antibody-producing plasma cells since they are also a broader component of the adaptive immune system. They are capable of functioning as antigen-presenting cells for T-cell activation and can produce an array of cytokines. Disturbances of peripheral B-cell homeostasis together with the formation of ectopic lymphoid neogenesis within the inflamed synovium appears to be a characteristic of patients with RA. Enhanced generation of memory B cells and autoreactive plasma cells producing IgM-RF and ACPA-IgG antibodies together with formation of immune complexes contribute to the maintenance of RA, whereas treatment with B-cell-directed anti-CD20 and CLTA4-Ig therapy provides clinical benefit.

scholarly journals Modulation of TAP-dependent antigen compartmentalization during human monocyte-to-DC differentiation

2019 ◽  
Vol 3 (6) ◽  
pp. 839-850 ◽  
Author(s):  
Marius Döring ◽  
Hanna Blees ◽  
Nicole Koller ◽  
Sabine Tischer-Zimmermann ◽  
Mathias Müsken ◽  
...  
Keyword(s):  
T Lymphocytes ◽  
Antigen Processing ◽  
Human Monocyte ◽  
Antigen Uptake ◽  
Adaptive Immune ◽  
Histocompatibility Complex ◽  
Adaptive Immune Cells ◽  
Early Endosomes ◽  
Secondary Lymphoid Organs

Abstract Dendritic cells (DCs) take up antigen in the periphery, migrate to secondary lymphoid organs, and present processed antigen fragments to adaptive immune cells and thus prime antigen-specific immunity. During local inflammation, recirculating monocytes are recruited from blood to the inflamed tissue, where they differentiate to macrophages and DCs. In this study, we found that monocytes showed high transporter associated with antigen processing (TAP)–dependent peptide compartmentalization and that after antigen pulsing, they were not able to efficiently stimulate antigen-specific T lymphocytes. Nevertheless, upon in vitro differentiation to monocyte-derived DCs, TAP-dependent peptide compartmentalization as well as surface major histocompatibility complex I turnover decreased and the cells efficiently restimulated T lymphocytes. Although TAP-dependent peptide compartmentalization decreased during DC differentiation, TAP expression levels increased. Furthermore, TAP relocated from early endosomes in monocytes to the endoplasmic reticulum (ER) and lysosomal compartments in DCs. Collectively, these data are compatible with the model that during monocyte-to-DC differentiation, the subcellular relocation of TAP and the regulation of its activity assure spatiotemporal separation of local antigen uptake and processing by monocytes and efficient T-lymphocyte stimulation by DCs.

Mechanism of Action of Antimalarial Drugs: Inhibition of Antigen Processing and Presentation

Lupus ◽  
1993 ◽  
Vol 2 (1_suppl) ◽  
pp. 9-12 ◽  
Author(s):  
Robert I. Fox ◽  
Ho-Il Kang
Keyword(s):  
T Cells ◽  
Endoplasmic Reticulum ◽  
Cell Surface ◽  
Mhc Class Ii ◽  
Antigen Processing ◽  
Antigenic Peptides ◽  
Underlying Basis ◽  
Peptide Complexes ◽  
Antigen Presenting ◽  
Antimalarial Compounds

Recent studies have elucidated the steps involved in the association of antigenic peptides with major histocompatibility complex (MHC) encoded proteins and have suggested how antimalarial compounds might influence this important site of immune activation. These steps of antigen presentation in the macrophage (or other antigen-presenting cells) include: (a) the partial proteolytic degradation of endogenous and exogenous proteins into peptides within the lysosome; (b) the synthesis of MHC class II (i.e. HLA-D associated) α, β, and invariant (Ii) chains in the endoplasmic reticulum; (c) the initial association of α-Ii and β-li chains in the endoplasmic reticulum and the transport of these complexes to the primary endosome; (d) the fusion of lysosomal vacuoles and endosomal vacuoles, allowing the mixtures of lysosomal enzymes, peptides, α–Ii and β–Ii; (e) the displacement of Ii chains by peptides to form α–β–peptide complexes in the endosome; and (f) the migration of α–β–peptide complexes to the macrophage cell surface where they can stimulate CD4 T cells, resulting in release of cytokines. A low pH is required for digestion of the protein by acidic hydrolases in the lysosome, for assembly of the α–β–peptide complex and for its transport to the cell surface. Chloroquine and hydroxychloroquine are weak diprotic bases that can diffuse across the cell membrane and raise the pH within cell vesicles. This background provides the underlying basis for the theory that antimalarials may act to prevent autoimmunity by the following putative mechanism. Antimalarial compounds may: (a) stabilize the α-Ii and β-Ii interactions and prevent low-affinity peptides from forming α–β–peptide complexes; and (b) interfere with the efficient movement of α-Ii, β-Ii and α–β–peptide complexes to the correct locations within the cell cytoplasm or to the cell surfaces. Decreased presentation of autoantigenic peptides by macrophages might then lead to downregulation of autoimmune CD4+ T cells and diminish release of cytokines associated with clinical and laboratory signs of autoimmune disease.

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