scholarly journals CD27 Promotes Survival of Activated T Cells and Complements CD28 in Generation and Establishment of the Effector T Cell Pool

2003 ◽  
Vol 198 (9) ◽  
pp. 1369-1380 ◽  
Author(s):  
Jenny Hendriks ◽  
Yanling Xiao ◽  
Jannie Borst
Keyword(s):  
T Cells ◽  
Influenza Virus ◽  
T Cell ◽  
T Cell Responses ◽  
Primary Response ◽  
T Cell Response ◽  
Activated T Cells ◽  
Effector T Cell ◽  
Cell Responses ◽  
Cell Pool

CD27, like CD28, acts in concert with the T cell receptor to support T cell expansion. Using CD27−/− mice, we have shown earlier that CD27 determines the magnitude of primary and memory T cell responses to influenza virus. Here, we have examined the relative contributions of CD27 and CD28 to generation of the virus-specific effector T cell pool and its establishment at the site of infection (the lung), using CD27−/−, CD28−/−, and CD27/CD28−/− mice. We find that primary and memory CD8+ T cell responses to influenza virus are dependent on the collective contribution of both receptors. In the primary response, CD27 and CD28 impact to a similar extent on expansion of virus-specific T cells in draining lymph nodes. CD27 is the principle determinant for accumulation of virus-specific T cells in the lung because it can sustain this response in CD28−/− mice. Unlike CD28, CD27 does not affect cell cycle activity, but promotes survival of activated T cells throughout successive rounds of division at the site of priming and may do so at the site of infection as well. CD27 was found to rescue CD28−/− T cells from death at the onset of division, explaining its capacity to support a T cell response in absence of CD28.

T-Cell and B-Cell Responses After Vaccination against Influenza Virus and Pneumococcus in Chronic Phase CML Patients Treated with Tyrosine Kinase Inhibitors.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2214-2214
Author(s):  
Hugues de Lavallade ◽  
Melanie Hart ◽  
Ian H Gabriel ◽  
Peter Kelleher ◽  
Abdullah Alsuliman ◽  
...  
Keyword(s):  
T Cells ◽  
Influenza Virus ◽  
T Cell ◽  
B Cell ◽  
Cell Response ◽  
T Cell Responses ◽  
T Cell Response ◽  
Healthy Controls ◽  
Cell Responses ◽  
Tnf Α

Abstract Abstract 2214 Poster Board II-191 Imatinib (IM), nilotinib and dasatinib are remarkably effective as single-agent treatments for chronic myeloid leukemia (CML) in chronic phase (CP). However little is known on their potential impact on the immune system and to date no human in vivo data are available. Data from in vitro and animal studies on the effects of IM on the immune response have been contradictory ranging from impaired antigen-specific T-cell response to enhanced stimulation of tolerant T cells. In addition few data are available to assess potential immunomodulatory effects of the second-generation tyrosine kinase inhibitors (TKIs) nilotinib and dasatinib. Dasatinib has inhibitory activity against a broader range of protein kinases than imatinib including the Src family kinases Lck and Fyn, both of which are associated with T-cell receptor primary signal transduction pathways. Dasatinib may also inhibit B cell signaling through the Lyn pathway which may have potential implications for immunotherapeutic strategies. An understanding of the effects of different TKIs on the immune response will have implications for the development of immunotherapeutic strategies. The aim of this study was to prospectively analyze humoral and cellular immune responses to vaccination against influenza virus (Flu) and Pneumococcus in CP-CML patients treated with IM, dasatinib or nilotinib compared to healthy controls. Fifty CP-CML patients on standard dose TKIs (IM, n=22; dasatinib, n=15; nilotinib, n=13) and 15 healthy controls were vaccinated against Flu (Inflenza vaccine Ph. Eur. 2008/2009, CSL biotherapies) and pneumococcus (Pneumovax II, Sanofi Pasteur MSD). Samples were taken pre and at 1 and 3 months post-vaccination. Titers of IgM and IgG anti-pneumococcal were determined using ELISA technology. A positive response was defined as an IgM serum titer >100 U/ml at 1 month; IgG response was considered positive for IgG >200 U/ml at 1 or 3 months. To investigate possible correlation between B cell subsets and the pneumococcal humoral response we evaluated IgM memory B cells (CD19+ CD27+ IgMhigh IgDlow) and switched memory B cell (CD19+ CD27+ IgM- IgD-) subsets using flow cytometry. We analyzed the immunological T-cell response to influenza virus both quantitatively and qualitatively using flow cytometry for intracellular TNF-α, IFN-gamma and IL2 and the cytotoxicity marker CD107a. A response was considered positive if there was a minimum of 0.10% Flu-specific TNF-α producing T-cells and the percentage of antigen-specific TNF-α producing T-cells was 2-fold or higher compared to pre-vaccination level. Preliminary results on 28 patients and 11 healthy controls have been analyzed thus far. Significantly fewer patients on TKIs mounted an anti-pneumococcal IgM response (IgM serum titer > 100 U/ml) compared to healthy controls (9/28 versus 8/11, p=0.033). An anti-pneumococcal IgM response was detected in 20%, 37.5% and 40% of CML patients on dasatinib, nilotinib and IM respectively, and in 73% of the healthy controls. Moreover, patients on TKI had significantly lower levels of anti-pneumococcal IgM at 1 month compared to healthy controls (median, 84.5 U/ml, range 5 to 200 vs 200 U/ml, range 15 to 200, p=0.006). At 1 month the median levels of IgM in patients on dasatinib, nilotinib and IM were 55 U/ml (range, 12 to 172), 87 U/ml (range, 8-138) and 90 U/ml (range, 5 to 200) respectively. We have so far analyzed CD8 and CD4 T cell responses to Flu vaccination in 15 patients on TKI and 5 healthy controls. Prior to vaccination, T cell responses against Flu were detected in 4/15 patients on TKI and 1/5 healthy controls, indicating pre-existing memory T cell responses to Flu. In these subjects the T-cell response to Flu did not increase significantly after vaccination and as such the response was defined as negative. A significant T-cell response to Flu was seen in 7/15 patients on TKI (median 0.28% TNF-α+CD4+ T cells, range 0.10–2.25%) and in 3/5 healthy control (median 0.79% TNF-α+CD4+T cells, range 0.12–1.34%). These preliminary results suggest that in patients with CML on TKIs the IgM B cell response to vaccination with Pneumovax is significantly impaired compared to healthy controls. We have as yet not detected a significant difference in T-cell response following vaccination with Flu in CML patients on TKIs compared to healthy controls. We are in the process of analyzing the remaining samples. Disclosures: Marin: Novartis: Consultancy, Research Funding.

scholarly journals 664 Pulmonary priming of tumor-reactive CD8+ T cells by DC1 is impaired by regulatory T cells

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A692-A692
Author(s):  
Maria Zagorulya ◽  
Duncan Morgan ◽  
Leon Yim ◽  
Brendan Horton ◽  
Elen Torres-Mejia ◽  
...  
Keyword(s):  
Lung Cancer ◽  
T Cells ◽  
T Cell ◽  
T Cell Responses ◽  
T Cell Response ◽  
List Type ◽  
Antigen Uptake ◽  
Treg Depletion ◽  
Effector T Cell ◽  
Cell Responses

BackgroundAlthough failure to respond to checkpoint blockade immunotherapies (CBT) is frequently associated with a lack of T cell infiltration into the tumor, emerging clinical data suggests that specifically in patients with lung cancer, T cell-inflamed tumors can also be resistant to therapy.1 Recent work by our group identified that immunotherapy resistance in a T cell-inflamed pre-clinical mouse model of lung cancer is driven by a lung cancer-specific CD8+ T cell dysfunctional program (TLdys), characterized by blunted production of IFNg and reduced cytolytic capacity. Intriguingly, this TLdysprogram is established during priming in the tumor-draining mediastinal lymph nodes (mLN). Understanding the lung-specific mechanisms blunting the activation of anti-tumor T cell responses could enable development of novel therapies needed to improve outcomes of patients with CBT-resistant T cell-inflamed lung cancer.MethodsTo study anti-tumor immune responses against lung tumors, a syngeneic lung cancer cell line (KP) was implanted orthotopically or subcutaneously into C57BL/6 mice. KP cells were engineered to express SIINFEKL and ZsGreen to enable studies of tumor-reactive T cells and antigen uptake by dendritic cells (DC).ResultsLung KP tumors led to the induction of tumor-reactive TLdys CD8+ T cells lacking CD25 and GzmB in the mLN, in contrast to subcutaneous KP tumors, which induced CD25high GzmBhigh tumor-reactive CD8+ T cells in the inguinal LN (iLN). Mouse models lacking DC1 revealed that DC1 are necessary to prime tumor-reactive CD8+ T cells in both LNs. Flow cytometry characterization of DC1 from LNs revealed equivalent levels of antigen load, but reduced levels of costimulatory molecules CD80, CD86 and the cytokine IL-12 in the mLN compared to iLN, suggesting a blunted stimulatory capacity in the lung setting. Regulatory T cell (Treg) depletion using FoxP3DTR mice rescued expression of effector T cell priming in tumor-draining mLN, suggesting that TLdys induction requires the presence of local Treg. Ex vivo co-cultures of antigen-specific CD8+ T cells with DC1 and Treg sorted from the mLN fully recapitulated the in vivo observation, suggesting that both DC1 and Treg are required and sufficient for TLdys induction. Blockade of the MHCII-dependent DC1:Treg interaction restored an effector-like profile of tumor-reactive CD8+ T cells.ConclusionsTreg restrain DC1 stimulatory function in the tumor-draining mLN, leading to the induction of lung cancer-specific dysfunction in tumor-reactive CD8+ T cells and thus rendering the T cell response refractory to CBT-mediated reinvigoration. Blockade of Treg:DC1 interactions can restore priming of lung cancer-reactive effector T cell responses.AcknowledgementsPew-Stewart Scholarship, Training grantReferenceHerbst RS, et al. Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients. Nature 2014;515:563–567.Ethics ApprovalAll mouse experiments in this study were approved by MIT's Committee on Animal Care (CAC) - DHHS Animal Welfare Assurance # D16-00078

scholarly journals Role of Thymic Output in Regulating CD8 T-Cell Homeostasis during Acute and Chronic Viral Infection

2005 ◽  
Vol 79 (15) ◽  
pp. 9419-9429 ◽  
Author(s):  
Nicole E. Miller ◽  
Jennifer R. Bonczyk ◽  
Yumi Nakayama ◽  
M. Suresh
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Cell Response ◽  
Viral Infections ◽  
T Cell Responses ◽  
Cd8 T Cell ◽  
T Cell Response ◽  
Cell Responses ◽  
Lcmv Infection

ABSTRACT Although it is well documented that CD8 T cells play a critical role in controlling chronic viral infections, the mechanisms underlying the regulation of CD8 T-cell responses are not well understood. Using the mouse model of an acute and chronic lymphocytic choriomeningitis virus (LCMV) infection, we have examined the relative importance of peripheral T cells and thymic emigrants in the elicitation and maintenance of CD8 T-cell responses. Virus-specific CD8 T-cell responses were compared between mice that were either sham thymectomized or thymectomized (Thx) at ∼6 weeks of age. In an acute LCMV infection, thymic deficiency did not affect either the primary expansion of CD8 T cells or the proliferative renewal and maintenance of virus-specific lymphoid and nonlymphoid memory CD8 T cells. Following a chronic LCMV infection, in Thx mice, although the initial expansion of CD8 T cells was normal, the contraction phase of the CD8 T-cell response was exaggerated, which led to a transient but striking CD8 T-cell deficit on day 30 postinfection. However, the virus-specific CD8 T-cell response in Thx mice rebounded quickly and was maintained at normal levels thereafter, which indicated that the peripheral T-cell repertoire is quite robust and capable of sustaining an effective CD8 T-cell response in the absence of thymic output during a chronic LCMV infection. Taken together, these findings should further our understanding of the regulation of CD8 T-cell homeostasis in acute and chronic viral infections and might have implications in the development of immunotherapy.

The cannabinoid WIN55212‐2 suppresses effector T cell responses and promotes regulatory T cells in human tonsils

Allergy ◽  
2021 ◽  
Author(s):  
Alba Angelina ◽  
Mario Pérez‐Diego ◽  
Angel Maldonado ◽  
Beate Rückert ◽  
Mübeccel Akdis ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
T Cell Responses ◽  
Effector T Cell ◽  
Cell Responses

scholarly journals Convergent epitope-specific T cell responses after SARS-CoV-2 infection and vaccination

2021 ◽  
Author(s):  
Anastasia A Minervina ◽  
Mikhail V Pogorelyy ◽  
Allison M Kirk ◽  
Emma Kaitlynn Allen ◽  
Kim J Allison ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Mononuclear Cells ◽  
T Cell Responses ◽  
T Cell Response ◽  
Critical Parameters ◽  
T Cell Memory ◽  
Cell Memory ◽  
Cell Responses ◽  
Depth Analysis

SARS-CoV-2 mRNA vaccines, including Pfizer/Biontech BNT162b2, were shown to be effective for COVID-19 prevention, eliciting both robust antibody responses in naive individuals and boosting pre-existing antibody levels in SARS-CoV-2-recovered individuals. However, the magnitude, repertoire, and phenotype of epitope-specific T cell responses to this vaccine, and the effect of vaccination on pre-existing T cell memory in SARS-CoV-2 convalescent patients, are still poorly understood. Thus, in this study we compared epitope-specific T cells elicited after natural SARS-CoV-2 infection, and vaccination of both naive and recovered individuals. We collected peripheral blood mononuclear cells before and after BNT162b2 vaccination and used pools of 18 DNA-barcoded MHC-class I multimers, combined with scRNAseq and scTCRseq, to characterize T cell responses to several immunodominant epitopes, including a spike-derived epitope cross-reactive to common cold coronaviruses. Comparing responses after infection or vaccination, we found that T cells responding to spike-derived epitopes show similar magnitudes of response, memory phenotypes, TCR repertoire diversity, and αβTCR sequence motifs, demonstrating the potency of this vaccination platform. Importantly, in COVID-19-recovered individuals receiving the vaccine, pre-existing spike-specific memory cells showed both clonal expansion and a phenotypic shift towards more differentiated CCR7-CD45RA+ effector cells. In-depth analysis of T cell receptor repertoires demonstrates that both vaccination and infection elicit largely identical repertoires as measured by dominant TCR motifs and receptor breadth, indicating that BNT162b2 vaccination largely recapitulates T cell generation by infection for all critical parameters. Thus, BNT162b2 vaccination elicits potent spike-specific T cell responses in naive individuals and also triggers the recall T cell response in previously infected individuals, further boosting spike-specific responses but altering their differentiation state. Overall, our study demonstrates the potential of mRNA vaccines to induce, maintain, and shape T cell memory through vaccination and revaccination.

scholarly journals Adrenergic signaling controls early transcriptional programs during CD8+ T cell responses to viral infection

2021 ◽  
Author(s):  
Leonardo Estrada ◽  
Didem Agac Cobanoglu ◽  
Aaron Wise ◽  
Robert Maples ◽  
Murat Can Cobanoglu ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
T Cell Responses ◽  
Cd8 T Cell ◽  
Receptor Activation ◽  
Cell Development ◽  
Primary Response ◽  
Cell Responses

Viral infections drive the expansion and differentiation of responding CD8+ T cells into variegated populations of cytolytic effector and memory cells. While pro-inflammatory cytokines and cell surface immune receptors play a key role in guiding T cell responses to infection, T cells are also markedly influenced by neurotransmitters. Norepinephrine is a key sympathetic neurotransmitter, which acts to suppress CD8 + T cell cytokine secretion and lytic activity by signaling through the beta2-adrenergic receptor (ADRB2). Although ADRB2 signaling is considered generally immunosuppressive, its role in regulating differentiation of effector T cells in response to infection has not been investigated. Using an adoptive transfer approach, we compared the expansion and differentiation of wild type (WT) to Adrb2-/- CD8 + T cells throughout the primary response to vesicular stomatitis virus (VSV) infection in vivo. We measured the dynamic changes in transcriptome profiles of antigen-specific CD8 + T cells as they responded to VSV. Within the first 7 days of infection, WT cells out-paced the expansion of Adrb2-/- cells, which correlated with reduced expression of IL-2 and the IL-2Ralpha; in the absence of ADRB2. RNASeq analysis identified over 300 differentially expressed genes that were both temporally regulated following infection and selectively regulated in WT vs Adrb2-/- cells. These genes contributed to major transcriptional pathways including cytokine receptor activation, signaling in cancer, immune deficiency, and neurotransmitter pathways. By parsing genes within groups that were either induced or repressed over time in response to infection, we identified three main branches of genes that were differentially regulated by the ADRB2. These gene sets were predicted to be regulated by specific transcription factors involved in effector T cell development, such as Tbx21 and Eomes. Collectively, these data demonstrate a significant role for ADRB2 signaling in regulating key transcriptional pathways during CD8 + T cells responses to infection that may dramatically impact their functional capabilities and downstream memory cell development.

scholarly journals Modulation of let-7 miRNAs controls the differentiation of effector CD8 T cells

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Alexandria C Wells ◽  
Keith A Daniels ◽  
Constance C Angelou ◽  
Eric Fagerberg ◽  
Amy S Burnside ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Lymphocytes ◽  
Cytotoxic T Lymphocytes ◽  
Cd8 T Cells ◽  
T Cell Responses ◽  
Cd8 T Cell ◽  
Cell Receptor ◽  
Activated T Cells ◽  
Cell Responses

The differentiation of naive CD8 T cells into effector cytotoxic T lymphocytes upon antigen stimulation is necessary for successful antiviral, and antitumor immune responses. Here, using a mouse model, we describe a dual role for the let-7 microRNAs in the regulation of CD8 T cell responses, where maintenance of the naive phenotype in CD8 T cells requires high levels of let-7 expression, while generation of cytotoxic T lymphocytes depends upon T cell receptor-mediated let-7 downregulation. Decrease of let-7 expression in activated T cells enhances clonal expansion and the acquisition of effector function through derepression of the let-7 targets, including Myc and Eomesodermin. Ultimately, we have identified a novel let-7-mediated mechanism, which acts as a molecular brake controlling the magnitude of CD8 T cell responses.

scholarly journals DNA gag/Adenovirus Type 5 (Ad5) gag and Ad5 gag/Ad5 gag Vaccines Induce Distinct T-Cell Response Profiles

2008 ◽  
Vol 82 (16) ◽  
pp. 8161-8171 ◽  
Author(s):  
Kara S. Cox ◽  
James H. Clair ◽  
Michael T. Prokop ◽  
Kara J. Sykes ◽  
Sheri A. Dubey ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Response ◽  
T Cell Responses ◽  
Adenovirus Type ◽  
T Cell Response ◽  
Cell Responses ◽  
Response Profiles ◽  
Adenovirus Type 5 ◽  
Hiv 1

ABSTRACT Results from Merck's phase II adenovirus type 5 (Ad5) gag/pol/nef test-of-concept trial showed that the vaccine lacked efficacy against human immunodeficiency virus (HIV) infection in a high-risk population. Among the many questions to be explored following this outcome are whether (i) the Ad5 vaccine induced the quality of T-cell responses necessary for efficacy and (ii) the lack of efficacy in the Ad5 vaccine can be generalized to other vector approaches intended to induce HIV type 1 (HIV-1)-specific T-cell responses. Here we present a comprehensive evaluation of the T-cell response profiles from cohorts of clinical trial subjects who received the HIV CAM-1 gag insert delivered by either a regimen with DNA priming followed by Ad5 boosting (n = 50) or a homologous Ad5/Ad5 prime-boost regimen (n = 70). The samples were tested using a statistically qualified nine-color intracellular cytokine staining assay measuring interleukin-2 (IL-2), tumor necrosis factor alpha, macrophage inflammatory protein 1β, and gamma interferon production and expression of CD107a. Both vaccine regimens induced CD4+ and CD8+ HIV gag-specific T-cell responses which variably expressed several intracellular markers. Several trends were observed in which the frequencies of HIV-1-specific CD4+ T cells and IL-2 production from antigen-specific CD8+ T cells in the DNA/Ad5 cohort were more pronounced than in the Ad5/Ad5 cohort. Implications of these results for future vaccine development will be discussed.

scholarly journals Activation-induced Markers Detect Vaccine-Specific CD4+ T Cell Responses Not Measured by Assays Conventionally Used in Clinical Trials

Vaccines ◽  
2018 ◽  
Vol 6 (3) ◽  
pp. 50 ◽  
Author(s):  
Georgina Bowyer ◽  
Tommy Rampling ◽  
Jonathan Powlson ◽  
Richard Morter ◽  
Daniel Wright ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Response ◽  
Viral Vectors ◽  
Comprehensive Evaluation ◽  
T Cell Responses ◽  
T Cell Response ◽  
Cell Responses ◽  
Vaccine Immunogenicity ◽  
Sensitivity Specificity

Immunogenicity of T cell-inducing vaccines, such as viral vectors or DNA vaccines and Bacillus Calmette-Guérin (BCG), are frequently assessed by cytokine-based approaches. While these are sensitive methods that have shown correlates of protection in various vaccine studies, they only identify a small proportion of the vaccine-specific T cell response. Responses to vaccination are likely to be heterogeneous, particularly when comparing prime and boost or assessing vaccine performance across diverse populations. Activation-induced markers (AIM) can provide a broader view of the total antigen-specific T cell response to enable a more comprehensive evaluation of vaccine immunogenicity. We tested an AIM assay for the detection of vaccine-specific CD4+ and CD8+ T cell responses in healthy UK adults vaccinated with viral vectored Ebola vaccine candidates, ChAd3-EBO-Z and MVA-EBO-Z. We used the markers, CD25, CD134 (OX40), CD274 (PDL1), and CD107a, to sensitively identify vaccine-responsive T cells. We compared the use of OX40+CD25+ and OX40+PDL1+ in CD4+ T cells and OX40+CD25+ and CD25+CD107a+ in CD8+ T cells for their sensitivity, specificity, and associations with other measures of vaccine immunogenicity. We show that activation-induced markers can be used as an additional method of demonstrating vaccine immunogenicity, providing a broader picture of the global T cell response to vaccination.

scholarly journals Archaeosome Adjuvant Overcomes Tolerance to Tumor-Associated Melanoma Antigens Inducing Protective CD8+T Cell Responses

2010 ◽  
Vol 2010 ◽  
pp. 1-13 ◽  
Author(s):  
Lakshmi Krishnan ◽  
Lise Deschatelets ◽  
Felicity C. Stark ◽  
Komal Gurnani ◽  
G. Dennis Sprott
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Regulatory Cells ◽  
T Cell Responses ◽  
T Cell Response ◽  
Antigen Delivery ◽  
Antigenic Peptides ◽  
Cell Responses ◽  
Tumor Protection ◽  
Melanoma Antigens

Vesicles comprised of the ether glycerolipids of the archaeonMethanobrevibacter smithii(archaeosomes) are potent adjuvants for evoking CD8+T cell responses. We therefore explored the ability of archaeosomes to overcome immunologic tolerance to self-antigens. Priming and boosting of mice with archaeosome-antigen evoked comparable CD8+T cell response and tumor protection to an alternate boosting strategy utilizing live bacterial vectors for antigen delivery. Vaccination with melanoma antigenic peptides TRP181-189and Gp10025-33delivered in archaeosomes resulted in IFN-γproducing antigen-specific CD8+T cells with strong cytolytic capability and protection against subcutaneous B16 melanoma. Targeting responses against multiple antigens afforded prolonged median survival against melanoma challenge. Entrapment of multiple peptides within the same vesicle or admixed formulations were both effective at evoking CD8+T cells against each antigen. Melanoma-antigen archaeosome formulations also afforded therapeutic protection against established B16 tumors when combined with depletion of T-regulatory cells. Overall, we demonstrate that archaeosome adjuvants constitute an effective choice for formulating cancer vaccines.

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