scholarly journals Invariant chain with an AP3 interacting sorting signal is sorted to late endosomal compartments and may improve MHC class I loading and presentation

2020 ◽  
Author(s):  
Ana Kucera ◽  
Nadia Mensali ◽  
Niladri Busan Pati ◽  
Else Marit Inderberg ◽  
Marit Renée Myhre ◽  
...  
Keyword(s):  
Cytotoxic T Cells ◽  
Physiological Role ◽  
Adaptor Proteins ◽  
T Cell Response ◽  
Invariant Chain ◽  
Peptide Epitope ◽  
Cross Presentation ◽  
Sorting Signals ◽  
Late Endosomes ◽  
Wild Type Counterpart

ABSTRACTInvariant chain (Ii) is traditionally known as the dedicated MHCII chaperone. Recent reports have broadened our understanding about various tasks that Ii plays including its physiological role in MHCI cross-presentation. Ii bound MHCI via the MHCII scaffolding CLIP peptide may facilitate MHCI trafficking to the endosomal pathway. The sorting function of Ii depends on two leucine-based sorting signals present in the cytoplasmic tail that acts as binding sites for the adaptor proteins AP-1/AP-2. Here we increased the Ii cross-presentation potency by replacing these with an AP3 motif resulting an efficient transport of Ii from TGN to late endosomes. We also replaced the CLIP region of li with a therapeutically relevant peptide, MART-1. We found the Ii AP3mutant-MART1 construct was capable of loading MHCI and stimulate specific T-cell response more efficiently than the wild type counterpart. The results show that Ii with an AP3 binding sorting motif carrying peptide epitope(s) can promote efficient antigen presentation to cytotoxic T cells (CTLs) independent of the ER located classical MHCI peptide loading machinery.

Neutrophils efficiently cross-prime naive T cells in vivo

Blood ◽  
2007 ◽  
Vol 110 (8) ◽  
pp. 2965-2973 ◽  
Author(s):  
Céline Beauvillain ◽  
Yves Delneste ◽  
Mari Scotet ◽  
Audrey Peres ◽  
Hugues Gascan ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Cytotoxic T Cells ◽  
Antigen Presenting Cells ◽  
Cd8 T Cell ◽  
T Cell Response ◽  
Cross Presentation ◽  
Antigen Presenting

Abstract Neutrophils are professional phagocytes that migrate early, in high number, to the infection sites. Our study has analyzed how neutrophils cross-present antigens and influence CD8+ T-cell responses. By using highly purified neutrophils from peritoneal exudates and bone marrow, we have shown that neutrophils cross-present ovalbumin to a CD8+ T-cell hybridoma and to naive CD8+ T cells from OT1 transgenic mice. Cross-presentation by neutrophils was TAP and proteasome dependent and was as efficient as in macrophages. Moreover, it actually occurred earlier than in professional antigen-presenting cells. Peritoneal exudate neutrophils from mice injected intraperitoneally with ovalbumin also cross-presented ovalbumin, proving that neutrophils take up and present exogenous antigens into major histocompatibility complex I (MHC I) molecules in vivo. We then evaluated the in vivo influence of antigen cross-presentation by neutrophils on CD8+ T-cell response using β2-microglobulin-deficient mice transferred with OT1 CD8+ T cells and injected with ovalbumin-pulsed neutrophils. Four days after neutrophil injection, OT1 cells proliferated and expressed effector functions (IFN-γ production and cytolysis). They also responded efficiently to a rechallenge with ovalbumin-pulsed dendritic cells in CFA. These data are the first demonstration that neutrophils cross-prime CD8+ T cells in vivo and suggest that they may constitute, together with professional antigen-presenting cells, an attractive target to induce cytotoxic T cells in vaccines.

scholarly journals An epidemic Zika virus isolate suppresses antiviral immunity by disrupting antigen presentation pathways

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Ryan D. Pardy ◽  
Stefanie F. Valbon ◽  
Brendan Cordeiro ◽  
Connie M. Krawczyk ◽  
Martin J. Richer
Keyword(s):  
T Cell ◽  
Zika Virus ◽  
Cell Response ◽  
Cd8 T Cell ◽  
T Cell Response ◽  
Cross Presentation ◽  
Cell Immunity ◽  
Asian Lineage ◽  
Insight Into ◽  
Host Tissues

AbstractZika virus (ZIKV) has emerged as an important global health threat, with the recently acquired capacity to cause severe neurological symptoms and to persist within host tissues. We previously demonstrated that an early Asian lineage ZIKV isolate induces a highly activated CD8 T cell response specific for an immunodominant epitope in the ZIKV envelope protein in wild-type mice. Here we show that a contemporary ZIKV isolate from the Brazilian outbreak severely limits CD8 T cell immunity in mice and blocks generation of the immunodominant CD8 T cell response. This is associated with a more sustained infection that is cleared between 7- and 14-days post-infection. Mechanistically, we demonstrate that infection with the Brazilian ZIKV isolate reduces the cross-presentation capacity of dendritic cells and fails to fully activate the immunoproteasome. Thus, our study provides an isolate-specific mechanism of host immune evasion by one Brazilian ZIKV isolate, which differs from the early Asian lineage isolate and provides potential insight into viral persistence associated with recent ZIKV outbreaks.

scholarly journals Relationship between invariant chain expression and major histocompatibility complex class II transport into early and late endocytic compartments.

1993 ◽  
Vol 177 (3) ◽  
pp. 583-596 ◽  
Author(s):  
P Romagnoli ◽  
C Layet ◽  
J Yewdell ◽  
O Bakke ◽  
R N Germain
Keyword(s):  
Major Histocompatibility Complex ◽  
Mhc Class Ii ◽  
Class Ii ◽  
Endocytic Pathway ◽  
Invariant Chain ◽  
Major Histocompatibility ◽  
Histocompatibility Complex ◽  
Late Endosomes ◽  
Early Endosomes ◽  
Endocytic Compartments

Invariant chain (Ii), which associates with major histocompatibility complex (MHC) class II molecules in the endoplasmic reticulum, contains a targeting signal for transport to intracellular vesicles in the endocytic pathway. The characteristics of the target vesicles and the relationship between Ii structure and class II localization in distinct endosomal subcompartments have not been well defined. We demonstrate here that in transiently transfected COS cells expressing high levels of the p31 or p41 forms of Ii, uncleaved Ii is transported to and accumulates in transferrin-accessible (early) endosomes. Coexpressed MHC class II is also found in this same compartment. These early endosomes show altered morphology and a slower rate of content movement to later parts of the endocytic pathway. At more moderate levels of Ii expression, or after removal of a highly conserved region in the cytoplasmic tail of Ii, coexpressed class II molecules are found primarily in vesicles with the characteristics of late endosomes/prelysosomes. The Ii chains in these late endocytic vesicles have undergone proteolytic cleavage in the lumenal region postulated to control MHC class II peptide binding. These data indicate that the association of class II with Ii results in initial movement to early endosomes. At high levels of Ii expression, egress to later endocytic compartments is delayed and class II-Ii complexes accumulate together with endocytosed material. At lower levels of Ii expression, class II-Ii complexes are found primarily in late endosomes/prelysosomes. These data provide evidence that the route of class II transport to the site of antigen processing and loading involves movement through early endosomes to late endosomes/prelysosomes. Our results also reveal an unexpected ability of intact Ii to modify the structure and function of the early endosomal compartment, which may play a role in regulating this processing pathway.

scholarly journals Cytotoxic T-cell-based vaccine against SARS-CoV2: a hybrid immunoinformatic approach

2021 ◽  
Author(s):  
Alexandru Tîrziu ◽  
Virgil Păunescu
Keyword(s):  
Immune Response ◽  
T Cell ◽  
Cytotoxic T Cells ◽  
Vaccination Campaign ◽  
Hla Class I ◽  
Class Ii ◽  
Docking Studies ◽  
Cytotoxic T Cell ◽  
Cross Presentation ◽  
Canonical Class

AbstractThis paper presents an alternative vaccination platform that provides long-term cellular immune protection mediated by cytotoxic T-cells. The immune response via cellular immunity creates superior resistance to viral mutations, which are currently the greatest threat to the global vaccination campaign. Furthermore, we also propose a safer, more facile and physiologically appropriate immunization method using either intra-nasal or oral administration. The underlying technology is an adaptation of synthetic long peptides (SLPs) previously used in cancer immunotherapy. SLPs comprising HLA class I and class II epitopes are used to stimulate antigen cross-presentation and canonical class II presentation by dendritic cells. The result is a cytotoxic T cell-mediated prompt and specific immune response against the virus-infected epithelia and a rapid and robust virus clearance. Peptides isolated from COVID-19 convalescent patients were screened for the best HLA population coverage and were tested for toxicity and allergenicity. 3D peptide folding followed by molecular docking studies provided positive results, suggesting a favourable antigen presentation.

scholarly journals Immunization with Chaperone-Peptide Complex Induces Low-Avidity Cytotoxic T Lymphocytes Providing Transient Protection against Herpes Simplex Virus Infection

2002 ◽  
Vol 76 (1) ◽  
pp. 136-141 ◽  
Author(s):  
Udayasankar Kumaraguru ◽  
Malgorzata Gierynska ◽  
Shanna Norman ◽  
Barry D. Bruce ◽  
Barry T. Rouse
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
T Cell ◽  
T Cell Responses ◽  
Recombinant Vaccinia Virus ◽  
T Cell Response ◽  
Peptide Epitope ◽  
Cell Responses ◽  
Simplex Virus ◽  
Shock Proteins

ABSTRACT Heat shock proteins loaded with viral peptides were shown to induce a CD8+ T cell response and confer protective immunity against challenge with herpes simplex virus (HSV). The delivery system consisted of recombinant human hsp70 coupled to the peptide SSIEFARL, which is the immunodominant peptide epitope, recognized by HSV specific T cells in C57BL/6 mice. Immunization resulted in CD8+ T-cell responses, measured by peptide-specific tetramers and peptide-induced intracellular gamma interferon expression and cytotoxicity, similar to responses resulting from immunization with a recombinant vaccinia virus that expressed SSIEFARL as a minigene (VvgB) and UV-inactivated HSV. However, the durability of the hsp70-SSIEFARL response was less than that resulting from VvgB and HSV immunization and in addition the CD8+ T-cell responses in the memory phase were functionally less effective. Mice challenged soon after immunization showed excellent immunity, but by 90 days postimmunization this had waned to be significantly less than the level of immunity in both VvgB- and HSV-immunized mice.

Regulation of Tim-3 function by binding to phosphatidylserine

2021 ◽  
Vol 478 (22) ◽  
pp. 3999-4004
Author(s):  
Lawrence P. Kane
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cd8 T Cells ◽  
Cell Activation ◽  
Transmembrane Protein ◽  
Cytotoxic T Cells ◽  
Cross Presentation ◽  
First Time

Tim-3 is a transmembrane protein that is highly expressed on subsets of chronically stimulated CD4+ helper and CD8+ cytotoxic T cells, with more transient expression during acute activation and infection. Tim-3 is also constitutively expressed by multiple types of myeloid cells. Like other TIM family members, Tim-3 can bind to phosphatidylserine displayed by apoptotic cells, and this interaction has been shown to mediate uptake of such cells by dendritic cells and cross-presentation of antigens to CD8+ T cells. In contrast, how the recognition of PS by Tim-3 might regulate the function of Tim-3+ T cells is not known. In their recent paper, Lemmon and colleagues demonstrate for the first time that recognition of PS by Tim-3 leads to enhanced T cell activation.

scholarly journals Internalization and endosomal degradation of receptor-bound antigens regulate the efficiency of cross presentation by human dendritic cells

Blood ◽  
2012 ◽  
Vol 120 (10) ◽  
pp. 2011-2020 ◽  
Author(s):  
Bithi Chatterjee ◽  
Anna Smed-Sörensen ◽  
Lillian Cohn ◽  
Cécile Chalouni ◽  
Richard Vandlen ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Vaccine Development ◽  
Mannose Receptor ◽  
Antigen Delivery ◽  
Cross Presentation ◽  
Late Endosomes ◽  
Early Endosomes ◽  
Antibody Conjugates ◽  
Human Dendritic Cells ◽  
Endocytic Compartments

Abstract Dendritic cells (DCs) can capture extracellular antigens and load resultant peptides on to MHC class I molecules, a process termed cross presentation. The mechanisms of cross presentation remain incompletely understood, particularly in primary human DCs. One unknown is the extent to which antigen delivery to distinct endocytic compartments determines cross presentation efficiency, possibly by influencing antigen egress to the cytosol. We addressed the problem directly and quantitatively by comparing the cross presentation of identical antigens conjugated with antibodies against different DC receptors that are targeted to early or late endosomes at distinct efficiencies. In human BDCA1+ and monocyte-derived DCs, CD40 and mannose receptor targeted antibody conjugates to early endosomes, whereas DEC205 targeted antigen primarily to late compartments. Surprisingly, the receptor least efficient at internalization, CD40, was the most efficient at cross presentation. This did not reflect DC activation by CD40, but rather its relatively poor uptake or intra-endosomal degradation compared with mannose receptor or DEC205. Thus, although both early and late endosomes appear to support cross presentation in human DCs, internalization efficiency, especially to late compartments, may be a negative predictor of activity when selecting receptors for vaccine development.

scholarly journals Oligomerization and Dissociation of AP-1 Adaptors Are Regulated by Cargo Signals and by ArfGAP1-induced GTP Hydrolysis

2005 ◽  
Vol 16 (10) ◽  
pp. 4745-4754 ◽  
Author(s):  
Daniel M. Meyer ◽  
Pascal Crottet ◽  
Bohumil Maco ◽  
Elena Degtyar ◽  
Dan Cassel ◽  
...  
Keyword(s):  
Molecular Weight ◽  
High Molecular Weight ◽  
Adaptor Proteins ◽  
Gtpase Activity ◽  
Gtpase Activating Protein ◽  
Gtp Hydrolysis ◽  
Sorting Signals ◽  
Initial Assembly ◽  
Cargo Sorting

The mechanism of AP-1/clathrin coat formation was analyzed using purified adaptor proteins and synthetic liposomes presenting tyrosine sorting signals. AP-1 adaptors recruited in the presence of Arf1·GTP and sorting signals were found to oligomerize to high-molecular-weight complexes even in the absence of clathrin. The appendage domains of the AP-1 adaptins were not required for oligomerization. On GTP hydrolysis induced by the GTPase-activating protein ArfGAP1, the complexes were disassembled and AP-1 dissociated from the membrane. AP-1 stimulated ArfGAP1 activity, suggesting a role of AP-1 in the regulation of the Arf1 “GTPase timer.” In the presence of cytosol, AP-1 could be recruited to liposomes without sorting signals, consistent with the existence of docking factors in the cytosol. Under these conditions, however, AP-1 remained monomeric, and recruitment in the presence of GTP was short-lived. Sorting signals allowed stable recruitment and oligomerization also in the presence of cytosol. These results suggest a mechanism whereby initial assembly of AP-1 with Arf1·GTP and ArfGAP1 on the membrane stimulates Arf1 GTPase activity, whereas interaction with cargo induces oligomerization and reduces the rate of GTP hydrolysis, thus contributing to efficient cargo sorting.

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