Pepstatin A-Sensitive Aspartic Proteases in Lysosome Are Involved in Degradation of the Invariant Chain and Antigen-Processing in Antigen Presenting Cells of Mice Infected with Leishmania major

2000 ◽  
Vol 276 (2) ◽  
pp. 693-701 ◽  
Author(s):  
Tianqian Zhang ◽  
Yoichi Maekawa ◽  
Koji Yasutomo ◽  
Hiroyuki Ishikawa ◽  
Baher Fawzy Nashed ◽  
...  
Keyword(s):  
Antigen Processing ◽  
Leishmania Major ◽  
Antigen Presenting Cells ◽  
Invariant Chain ◽  
Aspartic Proteases ◽  
Antigen Presenting ◽  
Pepstatin A

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 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.

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 Cathepsin B in Antigen-Presenting Cells Controls Mediators of the Th1 Immune Response during Leishmania major Infection

2014 ◽  
Vol 8 (9) ◽  
pp. e3194 ◽  
Author(s):  
Iris J. Gonzalez-Leal ◽  
Bianca Röger ◽  
Angela Schwarz ◽  
Tanja Schirmeister ◽  
Thomas Reinheckel ◽  
...  
Keyword(s):  
Immune Response ◽  
Cathepsin B ◽  
Leishmania Major ◽  
Antigen Presenting Cells ◽  
Major Infection ◽  
Antigen Presenting ◽  
Th1 Immune Response

scholarly journals Targeted Delivery of Antigen Processing Inhibitors to Antigen Presenting Cells via Mannose Receptors

2010 ◽  
Vol 5 (5) ◽  
pp. 461-476 ◽  
Author(s):  
Eun-Ang Raiber ◽  
Calogero Tulone ◽  
Yanjing Zhang ◽  
Luisa Martinez-Pomares ◽  
Emily Steed ◽  
...  
Keyword(s):  
Targeted Delivery ◽  
Antigen Processing ◽  
Antigen Presenting Cells ◽  
Antigen Presenting ◽  
Mannose Receptors

scholarly journals The Majority of H2-M3 Is Retained Intracellularly in a Peptide-Receptive State and Traffics to the Cell Surface in the Presence of N-Formylated Peptides

1999 ◽  
Vol 190 (3) ◽  
pp. 423-434 ◽  
Author(s):  
Nancy M. Chiu ◽  
Taehoon Chun ◽  
Miriam Fay ◽  
Manas Mandal ◽  
Chyung-Ru Wang
Keyword(s):  
Cell Surface ◽  
Antigen Processing ◽  
Cytotoxic T Cells ◽  
Antigen Presenting Cells ◽  
Cell Types ◽  
Surface Expression ◽  
Peptide Vaccination ◽  
Histocompatibility Complex ◽  
Antigen Presenting ◽  
Class Ib

We used a new monoclonal antibody (mAb 130) to analyze the intracellular trafficking and surface expression of H2-M3, the major histocompatibility complex class Ib molecule that presents N-formylated peptides to cytotoxic T cells. M3 surface expression is undetectable in most cell types due to the paucity of endogenous antigen. M3 is induced on the cell surface by addition of high-affinity N-formylated peptides from mitochondria and listeria. Peptide-induced M3 expression is most efficient on antigen presenting cells. Basal and inducible expression of M3 is transporter associated with antigen processing (TAP)-dependent, distinguishing M3 from the class Ib molecules TL and CD1. Unlike the expression of class Ia molecules and a previously described M3/Ld chimera, surface expression of M3 cannot be rescued by lowered temperature, suggesting that the α3 domain and transmembrane region of M3 may control trafficking. Pulse–chase analysis and use of trafficking inhibitors revealed a pool of empty M3 in the endoplasmic reticulum or early Golgi apparatus. Addition of exogenous peptide allows maturation with kinetics matching those of Dd. The lack of endogenous N-formylated peptide allows discovery of novel pathogen-derived peptides in normal antigen presenting cells. The nonpolymorphic nature of M3 and its ability to present bacterial antigens rapidly and dominantly make it an attractive target for peptide vaccination strategies.

scholarly journals Enhanced binding of peptide antigen to purified class II major histocompatibility glycoproteins at acidic pH.

1991 ◽  
Vol 174 (5) ◽  
pp. 1111-1120 ◽  
Author(s):  
P E Jensen
Keyword(s):  
Electrostatic Interactions ◽  
Antigen Processing ◽  
Ph Dependence ◽  
Peptide Binding ◽  
Antigen Presenting Cells ◽  
Class Ii ◽  
Major Histocompatibility ◽  
Hydrogen Ion Concentration ◽  
Peptide Antigens ◽  
Antigen Presenting

Helper T lymphocytes recognize peptide antigens stably associated with class II major histocompatibility complex (MHC) glycoproteins on the surface of antigen-presenting cells and serve to regulate a wide variety of immune responses. A previous study from our laboratory had demonstrated that the functional association of various peptide antigens with the antigen-presenting cell membrane was increased at pH 5 as compared to pH 7, consistent with the potential role of acidic endosomal compartments in antigen processing. The mechanism for this effect was not determined. In the present study, assays using purified class II glycoprotein were used to further define this mechanism. The potential requirement for pH-dependent interactions involving non-MHC membrane components was excluded in functional assays with purified class II reconstituted in artificial membranes containing only neutral phospholipids and cholesterol. The association of HEL(104-120) with I-Ed, and OVA(323-339) with I-Ad, was increased at pH 5, as measured by activation of specific T cell hybridomas. An enzyme immunoassay was developed to measure the binding of biotin-labeled peptides to purified class II in detergent micelles. The pH dependence of binding paralleled our previous functional results. Optimum binding of biotin-HEL(104-120) to I-Ed was observed at pH approximately 4.5, whereas maximum binding of biotin-Myo(106-118) to I-Ad occurred at pH approximately 5.5. The latter peptide also bound weakly to I-Ed, but with a pH dependence similar to that observed using HEL(104-120). Further experiments with biotin-HEL(104-120)/I-Ed indicated that both the apparent affinity and the apparent concentration of peptide-binding sites are increased as hydrogen ion concentration is increased from pH 7 to pH 5. The effect of pH in this range was largely reversible and was not associated with a change in peptide dissociation that could be measured with our assay system. Binding was not inhibited in the presence of 1.5 M NaCl, suggesting that electrostatic interactions between HEL(104-120) and I-Ed are not essential for binding. It is proposed that protonation of a critical group(s) in the class II molecule regulates its capacity to form stable complexes with peptide. However, this effect alone does not fully account for the rapid kinetics of peptide binding observed in experiments with intact antigen-presenting cells.

scholarly journals Intracellular Delivery of a Cytolytic T-Lymphocyte Epitope Peptide by Pertussis Toxin to Major Histocompatibility Complex Class I without Involvement of the Cytosolic Class I Antigen Processing Pathway

1999 ◽  
Vol 67 (2) ◽  
pp. 602-607 ◽  
Author(s):  
Nicholas H. Carbonetti ◽  
Teresa J. Irish ◽  
Carrie H. Chen ◽  
Colin B. O’Connell ◽  
Gregg A. Hadley ◽  
...  
Keyword(s):  
Major Histocompatibility Complex ◽  
Mhc Class I ◽  
T Lymphocyte ◽  
Pertussis Toxin ◽  
Antigen Processing ◽  
Antigen Presenting Cells ◽  
Class I ◽  
Histocompatibility Complex ◽  
Cytolytic T Lymphocyte ◽  
Antigen Presenting

ABSTRACT A CD8+ cytolytic T-lymphocyte (CTL) response to antigen-presenting cells generally requires intracellular delivery or synthesis of antigens in order to access the major histocompatibility complex (MHC) class I processing and presentation pathway. To test the ability of pertussis toxin (PT) to deliver peptides to the class I pathway for CTL recognition, we constructed fusions of CTL epitope peptides with a genetically detoxified derivative of PT (PT9K/129G). Two sites on the A (S1) subunit of PT9K/129G tolerated the insertion of peptides, allowing efficient assembly and secretion of the holotoxin fusion by Bordetella pertussis. Target cells incubated with these fusion proteins were specifically lysed by CTLs in vitro, and this activity was shown to be MHC class I restricted. The activity was inhibited by brefeldin A, suggesting a dependence on intracellular trafficking events, but was not inhibited by the proteasome inhibitors lactacystin andN-acetyl-l-leucyl-l-leucyl-l-norleucinal (LLnL). Furthermore, the activity was present in mutant antigen-presenting cells lacking the transporter associated with antigen processing, which transports peptides from the cytosol to the endoplasmic reticulum for association with MHC class I molecules. PT may therefore bypass the proteasome-dependent cytosolic pathway for antigen presentation and deliver epitopes to class I molecules via an alternative route.

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