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 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 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 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 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.

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 Follicular dendritic cells help resting B cells to become effective antigen-presenting cells: induction of B7/BB1 and upregulation of major histocompatibility complex class II molecules.

1993 ◽  
Vol 178 (6) ◽  
pp. 2055-2066 ◽  
Author(s):  
M H Kosco-Vilbois ◽  
D Gray ◽  
D Scheidegger ◽  
M Julius
Keyword(s):  
Dendritic Cells ◽  
Major Histocompatibility Complex ◽  
B Cells ◽  
Major Histocompatibility Complex Class ◽  
B Cell ◽  
Antigen Presenting Cells ◽  
Follicular Dendritic Cells ◽  
Complex Class ◽  
Histocompatibility Complex ◽  
Antigen Presenting

This study was designed to investigate whether follicular dendritic cells (FDC) can activate B cells to a state in which they can function as effective antigen-presenting cells (APC). High buoyant density (i.e., resting) B cells specific for 2,4-dinitro-fluorobenzene (DNP) were incubated with DNP-ovalbumin (OVA) bearing FDC, after which their capacity to process and present to an OVA-specific T cell clone was assessed. The efficacies of alternative sources of antigen and activation signals in the induction of B cell APC function were compared with those provided by FDC. Only FDC and Sepharose beads coated with anti-immunoglobulin (Ig)kappa monoclonal antibody provided the necessary stimulus. FDC carrying inappropriate antigens also induced B cell APC function in the presence of exogenous DNP-OVA. However, in circumstances where soluble DNP-OVA was limiting, FDC bearing complexes containing DNP, which could crosslink B cell Ig receptors, induced the most potent APC function. Analysis by flow cytometry revealed that within 24 h of coculture with FDC, a significant percentage of B cells increased in size and expressed higher levels of major histocompatibility complex class II. By 48 h, an upregulation of the costimulatory molecule, B7/BB1, occurred, but only when exposed to the FDC bearing DNP. Taken together, the results demonstrate that FDC have the capacity to activate resting B cells to a state in which they can function as APC for T cells. The stimuli that FDC provide may include: (a) an antigen-dependent signal that influences the upregulation of B7/BB1; and (b) possibly a signal independent of crosslinking mIg that results in Ig internalization. The relevance of these findings to the formation of germinal centers and maintenance of the humoral response is discussed.

scholarly journals CD26 Mediates Dissociation of Tollip and IRAK-1 from Caveolin-1 and Induces Upregulation of CD86 on Antigen-Presenting Cells

2005 ◽  
Vol 25 (17) ◽  
pp. 7743-7757 ◽  
Author(s):  
Kei Ohnuma ◽  
Tadanori Yamochi ◽  
Masahiko Uchiyama ◽  
Kunika Nishibashi ◽  
Satoshi Iwata ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
T Cell ◽  
Molecular Mechanisms ◽  
Interleukin 1 ◽  
Costimulatory Molecule ◽  
Antigen Presenting Cells ◽  
T Cell Proliferation ◽  
Caveolin 1 ◽  
Extracellular Region ◽  
Antigen Presenting

ABSTRACT CD26 is a T-cell costimulatory molecule with dipeptidyl peptidase IV enzyme activity in its extracellular region. We have previously reported that the addition of recombinant soluble CD26 resulted in enhanced proliferation of human T lymphocytes induced by the recall antigen tetanus toxoid (TT) via upregulation of CD86 on monocytes and that caveolin-1 was a binding protein of CD26, and the CD26-caveolin-1 interaction resulted in caveolin-1 phosphorylation (p-cav-1) as well as TT-mediated T-cell proliferation. However, the mechanism involved in this immune enhancement has not yet been elucidated. In the present work, we perform experiments to identify the molecular mechanisms by which p-cav-1 leads directly to the upregulation of CD86. Through proteomic analysis, we identify Tollip (Toll-interacting protein) and IRAK-1 (interleukin-1 receptor-associated serine/threonine kinase 1) as caveolin-1-interacting proteins in monocytes. We also demonstrate that following stimulation by exogenous CD26, Tollip and IRAK-1 dissociate from caveolin-1, and IRAK-1 is then phosphorylated in the cytosol, leading to the upregulation of CD86 via activation of NF-κB. Binding of CD26 to caveolin-1 therefore regulates signaling pathways in antigen-presenting cells to induce antigen-specific T-cell proliferation.

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