scholarly journals Dendritic cell-induced apoptosis of human cytomegalovirus-infected fibroblasts promotes cross-presentation of pp65 to CD8+ T cells

2008 ◽  
Vol 89 (1) ◽  
pp. 78-86 ◽  
Author(s):  
Marie Mandron ◽  
Hélène Martin ◽  
Béatrice Bonjean ◽  
Jacqueline Lulé ◽  
Eric Tartour ◽  
...  
Keyword(s):  
T Cells ◽  
Human Cytomegalovirus ◽  
Antigen Processing ◽  
Early Stage ◽  
Present Report ◽  
Necrosis Factor Alpha ◽  
Cross Presentation ◽  
Induced Apoptosis ◽  
Efficient Loading ◽  
The Impact

An efficient host response to human cytomegalovirus (HCMV) infection may depend on rapid sensing of the infection by the innate immune response prior to deployment of viral immunosubversive functions. Control of HCMV dissemination could be ensured by apoptosis of cells immediately following infection. In the present report, it is demonstrated that changes in the ratio of c-FLIP to FLICE contributed to early sensitivity of HCMV-infected MRC5 fibroblasts to tumour necrosis factor alpha (TNF-α), providing an innate response to infection. Dendritic cells (DCs) co-cultured with HCMV-infected MRC5 cells acquired the ability to secrete TNF-α in an amount sufficient to kill infected fibroblasts. Blockage of TNF-α binding to its receptor on MRC5 cells with soluble TNF-R reduced the number of dead, HCMV-infected fibroblasts ingested by DCs, thus highlighting the impact of the apoptotic state of infected cells for efficient loading of DCs. Those DCs loaded with antigens available early in infection, such as input virion-associated pp65, could then engage antigen processing for cross-presentation to specific CD8+ T cells. Cross-presentation was impaired when MRC5 cells were treated with the pan-caspase inhibitor ZVAD before co-culture with DCs. Altogether, our data suggest that the innate killing capacity of DCs at the early stage of infection plays a role in the activation of anti-HCMV CD8+ T cells.

scholarly journals Incoming Human Cytomegalovirus pp65 (UL83) Contained in Apoptotic Infected Fibroblasts Is Cross-Presented to CD8+ T Cells by Dendritic Cells

2000 ◽  
Vol 74 (21) ◽  
pp. 10018-10024 ◽  
Author(s):  
Géraldine Arrode ◽  
Claire Boccaccio ◽  
Jacqueline Lulé ◽  
Sophie Allart ◽  
Nathalie Moinard ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Human Cytomegalovirus ◽  
Matrix Protein ◽  
Immune Escape ◽  
Apoptotic Cells ◽  
Necrosis Factor Alpha ◽  
Cross Presentation ◽  
The Matrix ◽  
Antigen Presenting

ABSTRACT Human cytomegalovirus (HCMV) infection is well controlled mainly by cytotoxic CD8+ T lymphocytes (CTL) directed against the matrix protein pp65 despite the numerous immune escape mechanisms developed by the virus. Dendritic cells (DCs) are key antigen-presenting cells for the generation of an immune response which have the capacity to acquire antigens via endocytosis of apoptotic cells and thus present peptides to major histocompatibility complex class I-restricted T cells. We examined whether this mechanism could contribute to the activation of anti-pp65 CTL. In this study, we show that infection by HCMV AD169 induced sensitization of MRC5 fibroblasts to tumor necrosis factor alpha-mediated apoptosis very early after virus inoculation and that pp65 contained in apoptotic cells came from the delivery of the matrix protein into the cell. We observed that immature DCs derived from peripheral monocytes were not permissive to HCMV AD169 infection but were able to internalize pp65-positive apoptotic infected MRC5 cells. We then demonstrated that following exposure to these apoptotic bodies, DCs could activate HLA-A2- or HLA-B35-restricted anti-pp65 CTL, suggesting that they acquired and processed properly fibroblast-derived pp65. Together, our data suggest that cross-presentation of incoming pp65 contained in apoptotic cells may provide a quick and efficient way to prime anti-HCMV CD8+ T cells.

scholarly journals Cross-presentation of a TAP-independent signal peptide induces CD8 T immunity to escaped cancers but necessitates anchor replacement

2021 ◽  
Author(s):  
Koen A. Marijt ◽  
Lisa Griffioen ◽  
Laura Blijleven ◽  
Sjoerd. H. van der Burg ◽  
Thorbald van Hall
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cancer Cells ◽  
Cd8 T Cells ◽  
Antigen Processing ◽  
Signal Sequence ◽  
Cell Repertoire ◽  
Cross Presentation ◽  
Normal Tissues ◽  
Cell Immunity

AbstractCancer cells frequently display defects in their antigen-processing pathway and thereby evade CD8 T cell immunity. We described a novel category of cancer antigens, named TEIPP, that emerge on cancers with functional loss of the peptide pump TAP. TEIPPs are non-mutated neoantigens despite their ‘self’ origin by virtue of their absence on normal tissues. Here, we describe the development of a synthetic long peptide (SLP) vaccine for the most immunogenic TEIPP antigen identified thus far, derived from the TAP-independent LRPAP1 signal sequence. LRPAP121–30-specific CD8 T cells were present in blood of all tested healthy donors as well as patients with non-small cell lung adenocarcinoma. SLPs with natural flanking, however, failed to be cross-presented by monocyte-derived dendritic cells. Since the C-terminus of LRPAP121–30 is an unconventional and weakly binding serine (S), we investigated if replacement of this anchor would result in efficient cross-presentation. Exchange into a valine (V) resulted in higher HLA-A2 binding affinity and enhanced T cell stimulation. Importantly, CD8 T cells isolated using the V-variant were able to bind tetramers with the natural S-variant and respond to TAP-deficient cancer cells. A functional screen with an array of N-terminal and C-terminal extended SLPs pointed at the 24-mer V-SLP, elongated at the N-terminus, as most optimal vaccine candidate. This SLP was efficiently cross-presented and consistently induced a strong polyclonal LRPAP121–30-specific CD8 T cells from the endogenous T cell repertoire. Thus, we designed a TEIPP SLP vaccine from the LRPAP1 signal sequence ready for validation in clinical trials.

Transcriptional characterization of immune microenvironment and their prediction role for the prognosis of local advanced lung adenocarcinoma.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e20625-e20625
Author(s):  
Yuqiao Chen ◽  
Xinying Shi ◽  
Xue Song ◽  
Lingling Gao ◽  
Beibei Mao ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
Survival Data ◽  
Primary Tumor ◽  
Antigen Processing ◽  
Early Stage ◽  
Locally Advanced ◽  
Immune Microenvironment ◽  
Immune Related Genes ◽  
The Impact ◽  
Local Advanced

e20625 Background: The resection of early stage NSCLC offers patients the best hope of a cure. However, the recurrence rate post-resection remains high. As the mechanisms involved in the process is still not clear due to the unavailability of accurate targets, our study was aimed to integrate the impact of different immune context present in lung adenocarcinoma (LUAD) microenvironment on patients’ prognosis. Methods: RNA targeted sequencing was performed on 24 primary tumor specimens from the resected local advanced LUADs . Transcripts of 395 immune related genes expressed in FFPE tumor samples were analyzed. The limma package was used to analyze the different expressed genes (DEGs) between patients with different prognosis. The gene set variance analysis (GSVA) analysis was performed to explore gene sets enrichment related to the prognosis (PFS, progression free survival) post-resection. Results: 23 DEGs were detected in primary tumor between the better (PFS > 18months, n = 12 ) and worse (PFS≤18months, n = 12 ) prognosis group. The combined prediction model containing MPO, IL-6, CXCR2, FCGR3B, ADGRE5 could identify the favorable prognosis of patients. GSVA and Log Rank test of survival data demonstrated that the antigen processing and lymphocyte activation pathway enrichment may associate with better prognosis (p = 0.01), whereas higher Neutrophils cell infiltration in primary tumor demonstrated a shorter PFS (p = 0.008). Conclusions: In LUAD, the immune related genes such as MPO, IL-6, CXCR2, FCGR3B, ADGRE5, can effectively profile the landscape of tumor immune microenvironment and predict the survival in early stage of lung adenocarcinoma. Accordingly immune pathways were correlated with prognosis of these patients. Our findings suggest that immune-related RNA expression pattern in locally advanced LUAD may provide a potential predictive marker for early recurrence after surgical resection.

Impact of nicotine on the interplay between human periodontal ligament cells and CD4+ T cells

2016 ◽  
Vol 35 (9) ◽  
pp. 983-990 ◽  
Author(s):  
Xin Ge ◽  
Ying-Feng Liu ◽  
Yong Wong ◽  
Li-Zheng Wu ◽  
Ling Tan ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Viability ◽  
Periodontal Ligament ◽  
Tobacco Consumption ◽  
Periodontal Ligament Cells ◽  
Nicotine Treatment ◽  
Pdl Cells ◽  
Induced Apoptosis ◽  
The Impact

Periodontitis is a common infectious disease associated with destruction of periodontal ligaments and alveolar bones. CD4+ T cell-mediated immune response is involved in the progression of periodontitis. Tobacco consumption increases the risk of periodontal disease. However, the impact of nicotine on the interaction between human periodontal ligament (PDL) cells and CD4+ T cells remains unrevealed. Our study aims to investigate the effect of nicotine on PDL cells and the cocultured CD4+ T cells. The PDL cell cultures were established by explants from healthy individuals, exposed to nicotine or α-bungarotoxin (α-BTX), and incubated solely or in combination with CD4+ T cells. Afterwards, cell viability, secreted cytokines, and matrix metalloproteinases (MMPs) were evaluated. In monoculture of PDL cells, nicotine dramatically repressed cell viability and increased apoptosis. Meanwhile, α-BTX largely reversed the nicotine-induced apoptosis and increased viability of PDL cells. Compared with the monoculture, MMP-1, MMP-3, interleukin (IL)-1β, IL-6, IL-17, and IL-21 in supernatant of cocultures were markedly elevated after treatment with nicotine. Moreover, α-BTX significantly attenuated nicotine-triggered production of these components either in mono- or co-cultures. In addition, PDL cell-derived CXCL12 following nicotine treatment recruited CD4+ T cells. Above all, nicotine deteriorated periodontitis partially by promoting PDL cell–CD4+ T cell-mediated inflammatory response and matrix degradation.

scholarly journals Anti-IE1 CD4+ T-cell clones kill peptide-pulsed, but not human cytomegalovirus-infected, target cells

2007 ◽  
Vol 88 (9) ◽  
pp. 2441-2449 ◽  
Author(s):  
Sandra Delmas ◽  
Pierre Brousset ◽  
Danièle Clément ◽  
Emmanuelle Le Roy ◽  
Jean-Luc Davignon
Keyword(s):  
T Cells ◽  
T Cell ◽  
Human Cytomegalovirus ◽  
Antigen Processing ◽  
Hcmv Infection ◽  
Target Cells ◽  
T Cell Clones ◽  
Early Protein ◽  
Cell Clones ◽  
Precise Role

Cellular immunity plays a major role in the control of human cytomegalovirus (HCMV) infection. CD4+ T lymphocytes have been shown to contribute to this function but their precise role is a matter of debate. Although CD4+ T cells have been shown to kill target cells through the perforin/granzyme pathway, whether HCMV-specific CD4+ T cells are capable of killing HCMV-infected targets has not yet been documented. In the present paper, we have taken advantage of well established cellular reagents to address this issue. Human CD4+ T-cell clones specific for the major immediate-early protein IE1 were shown to perform perforin-based cytotoxicity against peptide-pulsed targets. However, when tested on infected anitgen presenting cell targets, cytotoxicity was not detectable, although gamma interferon (IFN-γ) production was significant. Furthermore, cytotoxicity against peptide-pulsed targets was inhibited by HCMV infection, whereas IFN-γ production was not modified, suggesting that antigen processing was not altered. Remarkably, degranulation of CD4+ T cells in the presence of infected targets was significant. Together, our data suggest that impaired cytotoxicity is not due to failure to recognize infected targets but rather to a mechanism specifically related to cytotoxicity.

scholarly journals Clinical and Immunological Insights on Severe, Adverse Neurotropic and Viscerotropic Disease following 17D Yellow Fever Vaccination

2009 ◽  
Vol 17 (1) ◽  
pp. 118-126 ◽  
Author(s):  
Maria Luiza Silva ◽  
Luçandra Ramos Espírito-Santo ◽  
Marina Angela Martins ◽  
Denise Silveira-Lemos ◽  
Vanessa Peruhype-Magalhães ◽  
...  
Keyword(s):  
T Cells ◽  
B Lymphocytes ◽  
Yellow Fever ◽  
Ex Vivo ◽  
Present Report ◽  
Suspected Case ◽  
Activated T Cells ◽  
Necrosis Factor Alpha ◽  
Tnf Α ◽  
Ifn Γ

ABSTRACT Yellow fever (YF) vaccines (17D-204 and 17DD) are well tolerated and cause very low rates of severe adverse events (YEL-SAE), such as serious allergic reactions, neurotropic adverse diseases (YEL-AND), and viscerotropic diseases (YEL-AVD). Viral and host factors have been postulated to explain the basis of YEL-SAE. However, the mechanisms underlying the occurrence of YEL-SAE remain unknown. The present report provides a detailed immunological analysis of a 23-year-old female patient. The patient developed a suspected case of severe YEL-AVD with encephalitis, as well as with pancreatitis and myositis, following receipt of a 17D-204 YF vaccination. The patient exhibited a decreased level of expression of Fc-γR in monocytes (CD16, CD32, and CD64), along with increased levels of NK T cells (an increased CD3+ CD16+/− CD56+/−/CD3+ ratio), activated T cells (CD4+ and CD8+ cells), and B lymphocytes. Enhanced levels of plasmatic cytokines (interleukin-6 [IL-6], IL-17, IL-4, IL-5, and IL-10) as well as an exacerbated ex vivo intracytoplasmic cytokine pattern, mainly observed within NK cells (gamma interferon positive [IFN-γ+], tumor necrosis factor alpha positive [TNF-α+], and IL-4 positive [IL-4+]), CD8+ T cells (IL-4+ and IL-5+), and B lymphocytes (TNF-α+, IL-4+, and IL-10+). The analysis of CD4+ T cells revealed a complex profile that consisted of an increased frequency of IL-12+ and IFN-γ+ cells and a decreased percentage of TNF-α+, IL-4+, and IL-5+ cells. Depressed cytokine synthesis was observed in monocytes (TNF-α+) following the provision of antigenic stimuli in vitro. These results support the hypothesis that a strong adaptive response and abnormalities in the innate immune system may be involved in the establishment of YEL-AND and YEL-AVD.

scholarly journals Proteomic analysis of necroptotic extracellular vesicles

2020 ◽  
Author(s):  
Inbar Shlomovitz ◽  
Gali Yanovich-Arad ◽  
Ziv Erlich ◽  
Liat Edry-Botzer ◽  
Sefi Zargarian ◽  
...  
Keyword(s):  
Extracellular Vesicles ◽  
Antigen Processing ◽  
Early Stage ◽  
Protein Composition ◽  
Kinase Domain ◽  
Adaptive Immune ◽  
And Control ◽  
High Degree ◽  
Antigen Processing And Presentation ◽  
The Impact

AbstractNecroptosis is a regulated and inflammatory form of cell death. We, and others, have previously reported that necroptotic cells release extracellular vesicles (EVs). We have found that necroptotic EVs are loaded with proteins, including the phosphorylated form of the key necroptosis-executing factor, mixed lineage kinase domain-like kinase (MLKL). However, neither the exact protein composition, nor the impact, of necroptotic EVs have been delineated. To characterize their content, EVs from necroptotic and untreated U937 cells were isolated and analyzed by mass spectrometry-based proteomics. A total of 3337 proteins were identified, sharing a high degree of similarity with exosome proteome databases, and clearly distinguishing necroptotic and control EVs. A total of 352 proteins were significantly upregulated in the necroptotic EVs. Among these were MLKL and caspase-8, as validated by immunoblot. Components of the ESCRTIII machinery and inflammatory signaling were also upregulated in the necroptotic EVs, as well as currently unreported components of vesicle formation and transport, and necroptotic signaling pathways. Moreover, we found that necroptotic EVs can be phagocytosed by macrophages to modulate cytokine and chemokine secretion. Finally, we uncovered that necroptotic EVs contain tumor neoantigens, and are enriched with components of antigen processing and presentation. In summary, our study reveals a new layer of regulation during the early stage of necroptosis, mediated by the secretion of specific EVs that influences the microenvironment and may instigate innate and adaptive immune responses. This study sheds light on new potential players in necroptotic signaling and its related EVs, and uncovers the functional tasks accomplished by the cargo of these necroptotic EVs.

scholarly journals Immunomodulatory Properties of a Viral Homolog of Human Interleukin-10 Expressed by Human Cytomegalovirus during the Latent Phase of Infection

2008 ◽  
Vol 82 (7) ◽  
pp. 3736-3750 ◽  
Author(s):  
C. Jenkins ◽  
W. Garcia ◽  
M. J. Godwin ◽  
J. V. Spencer ◽  
J. Lewis Stern ◽  
...  
Keyword(s):  
Human Cytomegalovirus ◽  
Neutralizing Antibodies ◽  
Latent Infection ◽  
Cell Types ◽  
Interleukin 10 ◽  
Immune Recognition ◽  
Necrosis Factor Alpha ◽  
Mhc Ii ◽  
Immunosuppressive Cytokine ◽  
The Impact

ABSTRACT Human cytomegalovirus (HCMV) establishes a latent infection in hematopoietic cells, from which it can reactivate to cause significant disease in immunocompromised individuals. HCMV expresses a functional homolog of the immunosuppressive cytokine interleukin-10 (termed cmvIL-10), and alternate splicing of the cmvIL-10 transcript results in expression of a latency-associated cmvIL-10 transcript (LAcmvIL-10). To determine whether LAcmvIL-10 encodes immunosuppressive functions, recombinant LAcmvIL-10 protein was generated, and its impact on major histocompatibility complex class II (MHC-II) expression was examined on granulocyte macrophage progenitor cells (GM-Ps) and monocytes. LAcmvIL-10 (and cmvIL-10) downregulated MHC-II on the surfaces of both cell types. This downregulation was associated with a decrease in total MHC-II protein and transcription of components of the MHC-II biosynthesis pathway. Unlike cmvIL-10, LAcmvIL-10 did not trigger phosphorylation of Stat3, and its ability to downregulate MHC-II was not blocked by neutralizing antibodies to the human IL-10 receptor, suggesting that LAcmvIL-10 either does not engage the cellular IL-10 receptor or utilizes it in a different manner from cmvIL-10. The impact of LAcmvIL-10 on dendritic cell (DC) maturation was also assessed. In contrast to cmvIL-10, LAcmvIL-10 did not inhibit the expression of costimulatory molecules CD40, CD80, and CD86 and the maturation marker CD83 on DCs, nor did it inhibit proinflammatory cytokines (IL-1α, IL-1β, IL-6 and tumor necrosis factor alpha). Thus, LAcmvIL-10 retains some, but not all, of the immunosuppressive functions of cmvIL-10. As GM-Ps and monocytes support latent infection, expression of LAcmvIL-10 may enable HCMV to avoid immune recognition and clearance during latency.

scholarly journals Placental Malaria-Associated Suppression of Parasite-Specific Immune Response in Neonates Has No Major Impact on Systemic CD4 T Cell Homeostasis

2011 ◽  
Vol 79 (7) ◽  
pp. 2801-2809 ◽  
Author(s):  
Valérie Soulard ◽  
Martin Amadoudji Zin ◽  
Catherine Fitting ◽  
Samad Ibitokou ◽  
Mayke Oesterholt ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Placental Malaria ◽  
Necrosis Factor Alpha ◽  
Content Type ◽  
Individual Level ◽  
Increased Risk ◽  
The Impact

ABSTRACTIn areas wherePlasmodium falciparumis endemic, pregnancy is associated with accumulation of infected red blood cells (RBCs) in the placenta, a condition referred to as placental malaria (PM). Infants born to PM-positive mothers are at an increased risk of malaria, which is putatively related to the transplacental passage of parasite-derived antigens, with consequent tolerization of the fetal immune system. Here we addressed the impact of PM on the regulation of neonatal T cell responses. We found that the frequency of regulatory CD25+CD127−/lowFoxp3+CD4+T cells was significantly decreased in neonates born to mothers with high levels ofP. falciparum-induced placental inflammation, consisting mainly of primigravid mothers. However, at the individual level, the ratio between regulatory and effector (CD25+CD127+Foxp3−) CD4+T cells was unaffected by PM. In addition, parasite-induced CD4+T cell activation and production of interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-α), and IL-10 were strongly reduced in neonates born to PM-positive mothers. Thus, our results show that active PM at delivery is associated with a marked suppression ofP. falciparum-specific cellular neonatal immune responses, affecting secretion of both pro- and anti-inflammatory cytokines. Additionally, our results suggest that, as in adults, effector and regulatory CD4+T cell populations are tightly coregulated in all neonates, irrespective of the maternal infection status.

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