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CD8+ T cell response mediates the therapeutic effects of oncolytic adenovirus in an immunocompetent mouse model
YaJun Yang,XiaoZhu Li,YaoHe Wang,ShengDian Wang
Chinese Science Bulletin , 2012, DOI: 10.1007/s11434-011-4875-3
Abstract: The role of anti-tumor immune responses in oncolytic adenoviral therapy has not been well studied due to lack of efficacious tumor model in immunocompetent mice. Here, we evaluated the contributions of immune components to the therapeutic effects of oncolytic adenoviruse in an immunocompetent murine tumor model permissive for infection and replication of adenovirus. We found that CD8+ T cells were critical mediator for antitumor efficacy by oncolytic adenovirus. Intratumoral viral therapy induced intensive infiltration of CD8+ T cells in tumor, increased tumor-specific IFN-γ (interferon-γ) production and CTL (cytotoxic T lymphocyte) activity of lymphocytes, and generated a long-term tumor-specific immune memory. Boosting CD8+ T cell responses by agonistic anti-4-1BB (cluster differentiation 137, CD137) antibody showed synergistic anticancer effects with oncolytic virotherapy. Our results provide insight into antitumor mechanisms of oncolytic adenovirus in addition to their direct oncolytic effect.
CD154 Blockade Alters Innate Immune Cell Recruitment and Programs Alloreactive CD8+ T Cells into KLRG-1high Short-Lived Effector T Cells  [PDF]
Ivana R. Ferrer, Maylene E. Wagener, Mingqing Song, Mandy L. Ford
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0040559
Abstract: CD154/CD40 blockade combined with donor specific transfusion remains one of the most effective therapies in prolonging allograft survival. Despite this, the mechanisms by which these pathways synergize to prevent rejection are not completely understood. Utilizing a BALB/c (H2-Kd) to B6 (H2-Kb) fully allogeneic skin transplant model system, we performed a detailed longitudinal analysis of the kinetics and magnitude of CD8+ T cell expansion and differentiation in the presence of CD154/CD40 pathway blockade. Results demonstrated that treatment with anti-CD154 vs. DST had distinct and opposing effects on activated CD44high CD62Llow CD8+ T cells in skin graft recipients. Specifically, CD154 blockade delayed alloreactive CD8+ T cell responses, while DST accelerated them. DST inhibited the differentiation of alloreactive CD8+ T cells into multi-cytokine producing effectors, while CD40/CD154 blockade led to the diminution of the KLRG-1low long-lived memory precursor population compared with either untreated or DST treated animals. Moreover, only CD154 blockade effectively inhibited CXCL1 expression and neutrophil recruitment into the graft. When combined, anti-CD154 and DST acted synergistically to profoundly diminish the absolute number of IFN-γ producing alloreactive CD8+ T cells, and intra-graft expression of inflammatory chemokines. These findings demonstrate that the previously described ability of anti-CD154 and DST to result in alloreactive T cell deletion involves both delayed kinetics of T cell expansion and differentiation and inhibited development of KLRG-1low memory precursor cells.
Recombinant Mammaglobin A Adenovirus-Infected Dendritic Cells Induce Mammaglobin A-Specific CD8+ Cytotoxic T Lymphocytes against Breast Cancer Cells In Vitro  [PDF]
Huixia Cui, Wenlu Zhang, Wei Hu, Kun Liu, Tong Wang, Nan Ma, Xiaohui Liu, Yunpeng Liu, Youhong Jiang
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0063055
Abstract: Mammaglobin A (MGBA) is a novel breast cancer-associated antigen almost exclusively over-expressed in primary and metastatic human breast cancers, making it a potential therapeutic target for breast cancer. The development of dendritic cell (DC)-induced tumor antigen specific CD8+ cytotoxic T lymphocytes (CTLs) may hold promise in cancer immunotherapy. In this study we constructed recombinant replication-defective adenoviral (Ad) vectors encoding MGBA and evaluated their ability to trigger anti-tumor immunity in vitro. DCs were isolated from the human peripheral blood monocyte cells (PBMCs) of two HLA-A33+ healthy female volunteers, and infected with adenovirus carrying MGBA cDNA (Ad-MGBA). After that, the Ad-MGBA-infected DCs were used to stimulate CD8+ CTLs in vitro and the latter was used for co-culture with breast cancer cell lines. The data revealed that infection with Ad-MGBA improved DC maturation and up-regulated the expression of co-stimulatory molecules and the secretion of interleukin-12 (IL-12), but down-regulated interleukin-10 (IL-10) secretion from DCs. Ad-MGBA-infected DC-stimulated CD8+CTLs displayed the highest cytotoxicity towards HLA-A33+/MGBA+ breast cancer MDA-MB-415 cells compared with other CD8+CTL populations, and compared with the cytotoxicity towards HLA-A33?/MGBA+ breast cancer HBL-100 cells and HLA-A33?/MGBA? breast cancer MDA-MB 231 cells. In addition, Ad-MGBA-infected DC-stimulated CD8+ CTLs showed a high level of IFNγ secretion when stimulated with HLA-A33+/MGBA+ breast cancer MDA-MB-415 cells, but not when stimulated with HLA-A33?/MGBA+ HBL-100 and HLA-A33?/MGBA?MDA-MB-231 cells. In addition, killing of CD8+CTLs against breast cancer was in a major histocompability complex (MHC)-limited pattern. Finally, the data also determined the importance of TNF-α in activating DCs and T cells. These data together suggest that MGBA recombinant adenovirus-infected DCs could induce specific anti-tumor immunity against MGBA+ breast cancers, which could provide a novel strategy in the immunotherapy of breast cancer.
Liver Is Able to Activate Na?ve CD8+ T Cells with Dysfunctional Anti-Viral Activity in the Murine System  [PDF]
John R. Lukens,Joseph S. Dolina,Taeg S. Kim,Robert S. Tacke,Young S. Hahn
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0007619
Abstract: The liver possesses distinct tolerogenic properties because of continuous exposure to bacterial constituents and nonpathogenic food antigen. The central immune mediators required for the generation of effective immune responses in the liver environment have not been fully elucidated. In this report, we demonstrate that the liver can indeed support effector CD8+ T cells during adenovirus infection when the T cells are primed in secondary lymphoid tissues. In contrast, when viral antigen is delivered predominantly to the liver via intravenous (IV) adenovirus infection, intrahepatic CD8+ T cells are significantly impaired in their ability to produce inflammatory cytokines and lyse target cells. Additionally, intrahepatic CD8+ T cells generated during IV adenovirus infection express elevated levels of PD-1. Notably, lower doses of adenovirus infection do not rescue the impaired effector function of intrahepatic CD8+ T cell responses. Instead, intrahepatic antigen recognition limits the generation of potent anti-viral responses at both priming and effector stages of the CD8+ T cell response and accounts for the dysfunctional CD8+ T cell response observed during IV adenovirus infection. These results also implicate that manipulation of antigen delivery will facilitate the design of improved vaccination strategies to persistent viral infection.
CTLA-4 blockade during dendritic cell based booster vaccination influences dendritic cell survival and CTL expansion  [cached]
Pedersen Anders E,Ronchese Franca
Journal of Immune Based Therapies and Vaccines , 2007, DOI: 10.1186/1476-8518-5-9
Abstract: Dendritic cells (DCs) are potent antigen-presenting cells and critical for the priming of CD8+ T cells. Therefore the use of these cells as adjuvant cells has been tested in a large number of experimental and clinical vaccination studies, in particular cancer vaccine studies. A number of protocols are emerging that combine vaccination with CTL expanding strategies, such as e.g. blockade of CTLA-4 signalling. On the other hand, the lifespan and in vivo survival of therapeutic DCs have only been addressed in a few studies, although this is of importance for the kinetics of CTL induction during vaccination. We have previously reported that DCs loaded with specific antigens are eliminated by antigen specific CTLs in vivo and that this elimination affects the potential for in vivo CTL generation. We now show that CTLA-4 blockade increases the number of DC vaccine induced LCMV gp33 specific CTLs and the lysis of relevant in vivo targets. However, the CTLA-4 blockage dependent expansion of CTLs also affect DC survival during booster DC injections and our data suggest that during a booster DC vaccine, the largest increase in CTL levels is already obtained during the first vaccination.
In Vivo CD8+ T-Cell Suppression of SIV Viremia Is Not Mediated by CTL Clearance of Productively Infected Cells  [PDF]
Joseph K. Wong equal contributor ,Matthew C. Strain,Rodin Porrata,Elizabeth Reay,Sumathi Sankaran-Walters,Caroline C. Ignacio,Theresa Russell,Satish K. Pillai,David J. Looney,Satya Dandekar equal contributor
PLOS Pathogens , 2010, DOI: 10.1371/journal.ppat.1000748
Abstract: The CD8+ T-cell is a key mediator of antiviral immunity, potentially contributing to control of pathogenic lentiviral infection through both innate and adaptive mechanisms. We studied viral dynamics during antiretroviral treatment of simian immunodeficiency virus (SIV) infected rhesus macaques following CD8+ T-cell depletion to test the importance of adaptive cytotoxic effects in clearance of cells productively infected with SIV. As previously described, plasma viral load (VL) increased following CD8+ T-cell depletion and was proportional to the magnitude of CD8+ T-cell depletion in the GALT, confirming a direct relationship between CD8+ T-cell loss and viral replication. Surprisingly, first phase plasma virus decay following administration of antiretroviral drugs was not slower in CD8+ T-cell depleted animals compared with controls indicating that the short lifespan of the average productively infected cell is not a reflection of cytotoxic T-lymphocyte (CTL) killing. Our findings support a dominant role for non-cytotoxic effects of CD8+ T-cells on control of pathogenic lentiviral infection and suggest that cytotoxic effects, if present, are limited to early, pre-productive stages of the viral life cycle. These observations have important implications for future strategies to augment immune control of HIV.
IN SILICO STUDY OF MHC, CD8 AND CTL BINDING REGIONS PRESENT IN STAPHYLOCOCCUS AUREUS AS IMMUNOGENS  [PDF]
Bernhardt Vidya G.,D'Souza Janita R. T.
International Journal of Research in Ayurveda and Pharmacy , 2011,
Abstract: Staphylococcus aureus vaccine is used to treat S. aureus infection that may not respond to conventional antibiotics therapy. It is believed to elicit cell mediated immune response. The study was carried out with the aid of computational tools and programs like NCBI, ClustalW, Hex 4.2, CASTp. We have predicted high conservation regions between S. aureus surface proteins and MHC I (Major Histocompatibility Complex) which were used to derive stable structures with MHC I by using Hex as a tool. Analysis of binding pockets by CASTp. Evaluation of stable docked complexes was done by docking with CD8. This complex was docked with the T-cell receptor. Docked structures were selected by minimum energy values. Sequence alignment of MHC 1 and staphylococcal antigens showed that a few antigens had highest similarity with MHC 1. The CASTp results showed the extracellular adhesion protein and collagen binding surface protein could be good elicitors of immunological response. Evaluation of some of the antigens by docking with CD8+ and MHC alpha domain confirm that not only do the proteins bind to MHC 1 but also bind to CD8+ molecules on the CTL (cytotoxic T lymphocyte) cell via the T-cell receptor. By understanding the MHC binding regions which are specific to the antigens present in ASL we can eluciate the immunogenic ability of ASL (autologous Staphylococcus lysate). The problem in subunit vaccine design of searching for antigenic regions in an antigen that can stimulate T cells and T cell epitopes has been overcome by using insilico methods that integrates prediction of peptide MHC I class binding, CD8+ and MHC I binding and identification of peptides that can stimulate CTLs.
CD8 T cell response in a phase I study of therapeutic vaccination of advanced NSCLC with allogeneic tumor cells secreting endoplasmic reticulum-chaperone gp96-Ig-peptide complexes  [PDF]
Luis E. Raez, Gail R. Walker, Paulette Baldie, Eva Fisher, Jorge E. Gomez, Khaled Tolba, Edgardo S. Santos, Eckhard R. Podack
Advances in Lung Cancer (ALC) , 2013, DOI: 10.4236/alc.2013.21002
Abstract: Antigen containing, allogeneic cells secreting the genetically modified protein and peptide-chaperone gp96-Ig cross, prime and expand antigen specific CD8 T cells with therapeutic antitumor activity in mice. In a first in man phase I study, we now report the results of therapeutic vaccination of non-small cell lung cancer (NSCLC) patients with an established, allogeneic non-small cell lung adenocarcinoma cell line secreting gp96-Ig. Advanced NSCLC-patients stage IIIB or IV of any histological subtype were enrolled and treated with up to 36 vaccinations over the course of 18 weeks. Primary endpoint was safety, secondary endpoints tumor response and overall survival. Measurement of tumor antigen specific CD8 CTL responses is precluded by the lack of known NSCLC associated antigens. Therefore, we measured patient CD8 T cell-IFN-γ responses to allo-antigens of the vaccine cells as surrogate for tumor antigen specific CD8 CTL. In 7 of 18 treated patients tumor growth was stabilized, however none of the 18 patients had an objective tumor response by RECIST criteria. Of 15 patients evaluable for immune response, 11 responded to vaccination with more than twofold increase in CD8-IFN-γ frequency above baseline. These patients had a median survival time of 16.5 months. Four patients who had no CD8 response above base line had survival times from 2.1 to 6.7 months. Our data are consistent with the concept that generation of CD8 CTL by therapeutic vaccination may delay tumor growth and progression and mediate prolonged survival even in the absence of objective tumor responses. Further studies will be required to test this concept and promising result.
Praziquantel Facilitates IFN-γ-Producing CD8+ T Cells (Tc1) and IL-17-Producing CD8+ T Cells (Tc17) Responses to DNA Vaccination in Mice  [PDF]
Qiang Zou, Xin Yao, Jin Feng, Zhinan Yin, Richard Flavell, Yanxin Hu, Guoxing Zheng, Jin Jin, Youmin Kang, Bing Wu, Xiaoxuan Liang, Congcong Feng, Hu Liu, Weiyi Li, Xianzheng Wang, Yumei Wen, Bin Wang
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0025525
Abstract: Background CD8+ cytotoxic T lymphocytes (CTLs) are crucial for eliminating hepatitis B virus (HBV) infected cells. DNA vaccination, a novel therapeutic strategy for chronic virus infection, has been shown to induce CTL responses. However, accumulated data have shown that CTLs could not be effectively induced by HBV DNA vaccination. Methodology/Principal Findings Here, we report that praziquantel (PZQ), an anti-schistoma drug, could act as an adjuvant to overcome the lack of potent CTL responses by HBV DNA vaccination in mice. PZQ in combination with HBV DNA vaccination augmented the induction of CD8+ T cell-dependent and HBV-specific delayed hypersensitivity responses (DTH) in C57BL/6 mice. Furthermore, the induced CD8+ T cells consisted of both Tc1 and Tc17 subtypes. By using IFN-γ knockout (KO) mice and IL-17 KO mice, both cytokines were found to be involved in the DTH. The relevance of these findings to HBV immunization was established in HBsAg transgenic mice, in which PZQ also augmented the induction of HBV-specific Tc1 and Tc17 cells and resulted in reduction of HBsAg positive hepatocytes. Adoptive transfer experiments further showed that PZQ-primed CD8+ T cells from wild type mice, but not the counterpart from IFN-γ KO or IL-17 KO mice, resulted in elimination of HBsAg positive hepatocytes. Conclusions/Significance Our results suggest that PZQ is an effective adjuvant to facilitate Tc1 and Tc17 responses to HBV DNA vaccination, inducing broad CD8+ T cell-based immunotherapy that breaks tolerance to HBsAg.
Active Evasion of CTL Mediated Killing and Low Quality Responding CD8+ T Cells Contribute to Persistence of Brucellosis  [PDF]
Marina Durward, Girish Radhakrishnan, Jerome Harms, Claire Bareiss, Diogo Magnani, Gary A. Splitter
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0034925
Abstract: Brucellosis is a common zoonotic disease that remains endemic in many parts of the world. Dissecting the host immune response during this disease provides insight as to why brucellosis is often difficult to resolve. We used a Brucella epitope specific in vivo killing assay to investigate the ability of CD8+ T cells to kill targets treated with purified pathogenic protein. Importantly, we found the pathogenic protein TcpB to be a novel effector of adaptive immune evasion by inhibiting CD8+ T cell killing of Brucella epitope specific target cells in mice. Further, BALB/c mice show active Brucella melitensis infection beyond one year, many with previously unreported focal infection of the urogenital area. A fraction of CD8+ T cells show a CD8+ Tmem phenotype of LFA-1hi, CD127hi, KLRG-1lo during the course of chronic brucellosis, while the CD8+ T cell pool as a whole had a very weak polyfunctional cytokine response with diminished co-expression of IFN-γ with TNFα and/or IL-2, a hallmark of exhaustion. When investigating the expression of these 3 cytokines individually, we observed significant IFN-γ expression at 90 and 180 days post-infection. TNFα expression did not significantly exceed or fall below background levels at any time. IL-2 expression did not significantly exceeded background, but, interestingly, did fall significantly below that of uninfected mice at 180 days post-infection. Brucella melitensis evades and blunts adaptive immunity during acute infection and our findings provide potential mechanisms for the deficit observed in responding CD8+ T cells during chronic brucellosis.
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