hDectin-1 Mediates Cross-Presentation of Epitopes Via the Cytosolic Pathway.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2313-2313
Author(s):  
Frank Grünebach ◽  
Markus M. Weck ◽  
Silke Appel ◽  
Daniela Werth ◽  
Christian Sinzger ◽  
...  
Keyword(s):  
Mhc Class I ◽  
Brefeldin A ◽  
Hla Class I ◽  
Class I ◽  
Apoptotic Cells ◽  
Down Regulation ◽  
Cross Presentation ◽  
Hla Class I Molecules ◽  
The Cross ◽  
Mhc Class I Molecules

Abstract Human (h)Dectin-1 is a member of the C-type-lectin-like receptor family that was shown to be the major receptor for fungal β-glucans and to play an important role in cellular responses mediated by these carbohydrates. It is mainly expressed on human DCs and macrophages. In our study, we observed that activation of monocyte-derived dendritic cells (MDCs) with TLR3 ligand (poly I:C) but not with TLR ligand 7/8 (R848) resulted in down-regulation of hDectin-1 expression and this down-regulation correlated with a reduced uptake of apoptotic cells in phagocytosis assays. In order to analyze the possible cross-presentation of engulfed antigens we used CMV infected human fibroblasts (HFF). We found that hDectin-1 is involved in the uptake of CMV-infected HFF leading to cross-presentation of CMV-derived peptides on MHC class I molecules and activation of CMV pp65-specific CD8+ T-lymphocytes. To further delineate the pathway leading to presentation, we pretreated MDCs with compounds that inhibit processing of antigens at defined steps during presentation. Cytosolic protein degradation is performed by the proteasome, a large multicatalytic protease complex. Lactacystin specifically inhibits the 20S and 26S proteasome activity by targeting the catalytic subunit. In standard 51Cr-release assays, addition of lactacystin completely inhibited the presentation of pp65-derived peptides indicating the involvement of the proteasome in these process. The fungal product brefeldin A blocks the MHC class I processing pathway by specifically inhibiting the vesicular egress from the ER and the Golgi complex. In line with previous findings, incubation with brefeldin A almost completely abolished the lysis of MDCs incubated with CMV+ HFF. To further analyze whether the cross-presentation of CMV-derived peptides on HLA class I molecules was dependent on lysosomal proteases, MDCs that were co-incubated with HFF as above were treated with the lysosomotropic agent chloroquine that prevents acidification of the lysosomal compartment involved in the exogenous pathway of antigen presentation. The addition of chloroquine had no effect on the cross-presentation of CMV-derived epitopes on HLA class I-molecules. Summarized, the data reported here show that hDectin-1 functions not only as a pattern recognition receptor in innate immunity but is also involved in the clearing of apoptotic cells and cross-presentation of cellular antigens on MHC class I molecules to specific CTLs.

scholarly journals ERAP1 Controls the Interaction of the Inhibitory Receptor KIR3DL1 With HLA-B51:01 by Affecting Natural Killer Cell Function

2021 ◽  
Vol 12 ◽  
Author(s):  
Silvia D’Amico ◽  
Valerio D’Alicandro ◽  
Mirco Compagnone ◽  
Patrizia Tempora ◽  
Giusy Guida ◽  
...  
Keyword(s):  
Mhc Class I ◽  
Cell Function ◽  
Nk Cell ◽  
Killer Cell ◽  
Cell Subset ◽  
Human Tumor ◽  
Hla Class I ◽  
Class I ◽  
Pharmacological Inhibition ◽  
Mhc Class I Molecules

The endoplasmic reticulum aminopeptidase ERAP1 regulates innate and adaptive immune responses by trimming peptides for presentation by major histocompatibility complex (MHC) class I molecules. Previously, we have shown that genetic or pharmacological inhibition of ERAP1 on murine and human tumor cell lines perturbs the engagement of NK cell inhibitory receptors Ly49C/I and Killer-cell Immunoglobulin-like receptors (KIRs), respectively, by their specific ligands (MHC class I molecules), thus leading to NK cell killing. However, the effect of ERAP1 inhibition in tumor cells was highly variable, suggesting that its efficacy may depend on several factors, including MHC class I typing. To identify MHC class I alleles and KIRs that are more sensitive to ERAP1 depletion, we stably silenced ERAP1 expression in human HLA class I-negative B lymphoblastoid cell line 721.221 (referred to as 221) transfected with a panel of KIR ligands (i.e. HLA-B*51:01, -Cw3, -Cw4 and -Cw7), or HLA-A2 which does not bind any KIR, and tested their ability to induce NK cell degranulation and cytotoxicity. No change in HLA class I surface expression was detected in all 221 transfectant cells after ERAP1 depletion. In contrast, CD107a expression levels were significantly increased on NK cells stimulated with 221-B*51:01 cells lacking ERAP1, particularly in the KIR3DL1-positive NK cell subset. Consistently, genetic or pharmacological inhibition of ERAP1 impaired the recognition of HLA-B*51:01 by the YTS NK cell overexpressing KIR3DL1*001, suggesting that ERAP1 inhibition renders HLA-B*51:01 molecules less eligible for binding to KIR3DL1. Overall, these results identify HLA-B*51:01/KIR3DL1 as one of the most susceptible combinations for ERAP1 inhibition, suggesting that individuals carrying HLA-B*51:01-like antigens may be candidates for immunotherapy based on pharmacological inhibition of ERAP1.

scholarly journals Long-Peptide Cross-Presentation by Human Dendritic Cells Occurs in Vacuoles by Peptide Exchange on Nascent MHC Class I Molecules

2016 ◽  
Vol 196 (4) ◽  
pp. 1711-1720 ◽  
Author(s):  
Wenbin Ma ◽  
Yi Zhang ◽  
Nathalie Vigneron ◽  
Vincent Stroobant ◽  
Kris Thielemans ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Mhc Class I ◽  
Class I ◽  
Cross Presentation ◽  
Peptide Exchange ◽  
Human Dendritic Cells ◽  
Mhc Class I Molecules

IFN-α enhances cross-presentation in human dendritic cells by modulating antigen survival, endocytic routing, and processing

Blood ◽  
2012 ◽  
Vol 119 (6) ◽  
pp. 1407-1417 ◽  
Author(s):  
Francesca Spadaro ◽  
Caterina Lapenta ◽  
Simona Donati ◽  
Laura Abalsamo ◽  
Vincenzo Barnaba ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Mhc Class I ◽  
Cd8 T Cells ◽  
Tumor Development ◽  
Class I ◽  
Cross Presentation ◽  
The Cross ◽  
Human Dendritic Cells

Abstract Cross-presentation allows antigen-presenting cells to present exogenous antigens to CD8+ T cells, playing an essential role in controlling infections and tumor development. IFN-α induces the rapid differentiation of human mono-cytes into dendritic cells, known as IFN-DCs, highly efficient in mediating cross-presentation, as well as the cross-priming of CD8+ T cells. Here, we have investigated the mechanisms underlying the cross-presentation ability of IFN-DCs by studying the intracellular sorting of soluble ovalbumin and nonstructural-3 protein of hepatitis C virus. Our results demonstrate that, independently from the route and mechanism of antigen entry, IFN-DCs are extraordinarily competent in preserving internalized proteins from early degradation and in routing antigens toward the MHC class-I processing pathway, allowing long-lasting, cross-priming capacity. In IFN-DCs, both early and recycling endosomes function as key compartments for the storage of both antigens and MHC-class I molecules and for proteasome- and transporter-associated with Ag processing–dependent auxiliary cross-presentation pathways. Because IFN-DCs closely resemble human DCs naturally occurring in vivo in response to infections and other danger signals, these findings may have important implications for the design of vaccination strategies in neoplastic or chronic infectious diseases.

scholarly journals Constitutive versus Activation-dependent Cross-Presentation of Immune Complexes by CD8+ and CD8− Dendritic Cells In Vivo

2002 ◽  
Vol 196 (6) ◽  
pp. 817-827 ◽  
Author(s):  
Joke M.M. den Haan ◽  
Michael J. Bevan
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Mhc Class I ◽  
Cd8 T Cells ◽  
Immune Complexes ◽  
Class I ◽  
Cross Presentation ◽  
Deficient Mice ◽  
Mhc Class I Molecules

Murine splenic dendritic cells (DCs) can be divided into two subsets based on CD8α expression, but the specific role of each subset in stimulation of T cells is largely unknown. An important function of DCs is the ability to take up exogenous antigens and cross-present them in the context of major histocompatibility complex (MHC) class I molecules to CD8+ T cells. We previously demonstrated that, when cell-associated ovalbumin (OVA) is injected into mice, only the CD8+ DC subset cross-presents OVA in the context of MHC class I. In contrast to this selectivity with cell-associated antigen, we show here that both DC subsets isolated from mice injected with OVA/anti-OVA immune complexes (OVA-IC) cross-present OVA to CD8+ T cells. The use of immunoglobulin G Fc receptor (FcγR) common γ-chain–deficient mice revealed that the cross-presentation by CD8− DCs depended on the expression of γ-chain–containing activating FcγRs, whereas cross-presentation by CD8+ DCs was not reduced in γ-chain–deficient mice. These results suggest that although CD8+ DCs constitutively cross-present exogenous antigens in the context of MHC class I molecules, CD8− DCs only do so after activation, such as via ligation of FcγRs. Cross-presentation of immune complexes may play an important role in autoimmune diseases and the therapeutic effect of antitumor antibodies.

scholarly journals Targeting the coding sequence: opposing roles in regulating classical and non-classical MHC class I molecules by miR-16 and miR-744

2020 ◽  
Vol 8 (1) ◽  
pp. e000396
Author(s):  
Michael Friedrich ◽  
Christoforos K Vaxevanis ◽  
Katharina Biehl ◽  
Anja Mueller ◽  
Barbara Seliger
Keyword(s):  
Mhc Class I ◽  
Binding Sites ◽  
Hla Class I ◽  
The Cancer Genome Atlas ◽  
Class I ◽  
Atlas Data ◽  
Candidate Mirnas ◽  
Cancer Genome Atlas ◽  
Mhc Class I Molecules ◽  
Genome Atlas

BackgroundTo control gene expression, microRNAs (miRNAs) are of key importance and their deregulation is associated with the development and progression of various cancer types. In this context, a discordant messenger RNA/protein expression pointing to extensive post-transcriptional regulation of major histocompatibility complex (MHC) class I molecules was already shown. However, only a very limited number of miRNAs targeting these molecules have yet been identified. Despite an increasing evidence of coding sequence (CDS)-located miRNA binding sites, there exists so far, no detailed study of the interaction of miRNAs with the CDS of MHC class I molecules.MethodsUsing an MS2-tethering approach in combination with small RNA sequencing, a number of putative miRNAs binding to the CDS of human leukocyte antigen (HLA)-G were identified. These candidate miRNAs were extensively screened for their effects in the HLA-G-positive JEG3 cell line. Due to the high sequence similarity between HLA-G and classical MHC class I molecules, the impact of HLA-G candidate miRNAs on HLA class I surface expression was also analyzed. The Cancer Genome Atlas data were used to correlate candidate miRNAs and HLA class I gene expression.ResultsTransfection of candidate miRNAs revealed that miR-744 significantly downregulates HLA-G protein levels. In contrast, overexpression of the candidate miRNAs miR-15, miR-16, and miR-424 sharing the same seed sequence resulted in an unexpected upregulation of HLA-G. Comparable results were obtained for classical MHC class I members after transfection of miRNA mimics into HEK293T cells. Analyses of The Cancer Genome Atlas data sets for miRNA and MHC class I expression further validated the results.ConclusionsOur data expand the knowledge about MHC class I regulation and showed for the first time an miRNA-dependent control of MHC class I antigens mediated by the CDS. CDS-located miRNA binding sites could improve the general use of miRNA-based therapeutic approaches as these sites are highly independent of structural variations (e.g. mutations) in the gene body. Surprisingly, miR-16 family members promoted MHC class I expression potentially in a gene activation-like mechanism.

scholarly journals Regulation of T cell lymphokine production by killer cell inhibitory receptor recognition of self HLA class I alleles.

1996 ◽  
Vol 184 (2) ◽  
pp. 789-794 ◽  
Author(s):  
A D'Andrea ◽  
C Chang ◽  
J H Phillips ◽  
L L Lanier
Keyword(s):  
T Cells ◽  
T Cell ◽  
Mhc Class I ◽  
Cytokine Production ◽  
Killer Cell ◽  
Hla Class I ◽  
Class I ◽  
Target Cells ◽  
T Cell Clone ◽  
Mhc Class I Molecules

The killer cell inhibitory receptors (KIRs) are surface glycoproteins expressed by natural killer (NK) and T cells that specifically recognize defined groups of polymorphic human histocompatibility leukocyte antigen (HLA) class I molecules. Interactions between KIRs on NK or T cells and major histocompatibility complex (MHC) class I molecules on potential target cells inhibit cell-mediated cytotoxicity, presumably by delivering a negative signal preventing lymphocyte activation. In this study we examined whether KIRs also regulate cytokine production induced in response to T cell receptor-dependent T cell activation. CD4+ and CD8+ T cell clones were stimulated by bacterial superantigens in the presence or absence of monoclonal antibodies (mAbs) against the KIR NKB1 or MHC class I molecules, and production of tumor necrosis factor alpha and interferon gamma was evaluated. When bacterial superantigen was presented by an autologous antigen-presenting cell (APC) to a KIR+ T cell clone, cytokine production was always enhanced in the presence of anti-MHC class I mAb. Similarly, anti-KIR mAb also augmented cytokine production, provided that the APC expressed a HLA class I allele recognized by the KIR. These results suggest that recognition of autologous MHC class I molecules by KIR+ T cells provides a regulatory mechanism acting to modulate the potency of their responses to antigenic challenge.

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