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DC-STAMP knock-down deregulates cytokine production and T-cell stimulatory capacity of LPS-matured dendritic cells
Anna Sanecka, Marleen Ansems, Amy C Prosser, Katharina Danielski, Kathrin Warner, Martijn H den Brok, Bastiaan JH Jansen, Dagmar Eleveld-Trancikova, Gosse J Adema
BMC Immunology , 2011, DOI: 10.1186/1471-2172-12-57
Abstract: We demonstrate that DC-STAMP knock-down mBMDCs secrete less IL-6, IL-12, TNF-α and IL-10 while IL-1 production is enhanced. Moreover, LPS-matured DC-STAMP knock-down mBMDCs show impaired T cell activation potential and induction of Th1 responses in an alloreaction.We show that DC-STAMP plays an important role in cytokine production by mBMDCs following LPS exposure. Our results reveal a novel function of DC-STAMP in regulating DC-initiated immune responses.Dendritic cells (DCs) are professional antigen presenting cells (APC) that play a central role in innate and adaptive immunity. DCs, armed with a wide range of receptors that sense danger signals and scavenge antigens in the surrounding environment, constantly scan our body. Antigen uptake in the presence of inflammation and danger signals results in DC maturation. In this active state DCs are able to efficiently induce immune responses [1]. On the other hand, in the absence of danger signals DCs regulate tolerance to self-antigens in order to prevent autoimmunity.During maturation DCs upregulate costimulatory molecules such as CD40, CD80 and CD86 as well as MHC class II, which allows for effective antigen presentation to na?ve T cells. Furthermore, mature DCs produce and secrete proinflammatory cytokines and chemokines to attract and activate innate effector cells as well as to direct the development of specific T helper (Th) subsets [2]. High levels of IL-12 will induce differentiation of na?ve CD4+ T cells into Th1 cells while blocking the development of the Th2 lineage [3]. To prime Th2 responses IL-4 produced by Th2 cells themselves, NKT cells, eosinophils or basophils is needed [4,5]. Additionally, IL-1 has a positive influence on expansion of the murine Th2 cells [6]. The murine Th17 T-cell subset efficiently develops in the presence of the proinflammatory cytokines IL-6 and TGF-β [7].Due to their immunoregulatory capacities DCs are a promising tool for immunotherapy. Indeed, DC-based therapies are currently
Global Stability of HIV Infection of CD4+ T Cells and Macrophages with CTL Immune Response and Distributed Delays  [PDF]
A. M. Elaiw,R. M. Abukwaik,E. O. Alzahrani
Computational and Mathematical Methods in Medicine , 2013, DOI: 10.1155/2013/653204
Abstract: We study the global stability of a human immunodeficiency virus (HIV) infection model with Cytotoxic T Lymphocytes (CTL) immune response. The model describes the interaction of the HIV with two classes of target cells, CD4+ T cells and macrophages. Two types of distributed time delays are incorporated into the model to describe the time needed for infection of target cell and virus replication. Using the method of Lyapunov functional, we have established that the global stability of the model is determined by two threshold numbers, the basic reproduction number and the immune response reproduction number . We have proven that, if , then the uninfected steady state is globally asymptotically stable (GAS), if , then the infected steady state without CTL immune response is GAS, and, if , then the infected steady state with CTL immune response is GAS. 1. Introduction One of the most diseases that have attracted the attention of many mathematicians is the acquired immunodeficiency syndrome (AIDS) caused by human immunodeficiency virus (HIV). HIV infects the CD4+ T cell which plays the central role in the immune system. Mathematical modeling and model analysis of HIV dynamics are important to discover the dynamical behaviors of the viral infection process and estimating key parameter values which leads to development of efficient antiviral drug therapies. Several mathematical models have been proposed to describe the HIV dynamics with CD4+ T cells [1–15]. In these papers, the Cytotoxic T Lymphocytes (CTL) immune response was not taken into account. The role of CTL is universal and necessary to eliminate or control the disease during viral infections. In particular, as a part of innate response, CTL plays a particularly important rate in antiviral defense by attacking infected cells. The basic HIV infection model which takes into consideration the CTL immune response has been proposed in [16] as The state variables describe the plasma concentrations of , the uninfected CD4+ T cells; , the infected CD4+ T cells; , the free virus particles; and , the CTL cells at time . Here, (1) describes the population dynamics of the uninfected CD4+ T cells, where represents the rate of new uninfected cells that are generated from sources within the body, is the death rate constant, and is the infection rate constant at which a target cell becomes infected via contacting with virus. Equation (2) describes the population dynamics of the infected CD4+ T cells and shows that they die with rate constant and are killed by the CTL immune response with rate constant . Equation (3)
IRX-2, a Novel Immunotherapeutic, Enhances Functions of Human Dendritic Cells  [PDF]
Bastian Schilling, Malgorzata Harasymczuk, Patrick Schuler, James Egan, Soldano Ferrone, Theresa L. Whiteside
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0047234
Abstract: Background In a recent phase II clinical trial for HNSCC patients, IRX-2, a cell-derived biologic, promoted T-cell infiltration into the tumor and prolonged overall survival. Mechanisms responsible for these IRX-2-mediated effects are unknown. We hypothesized that IRX-2 enhanced tumor antigen-(TA)-specific immunity by up-regulating functions of dendritic cells (DC). Methodology/Principal Findings Monocyte-derived DC obtained from 18 HNSCC patients and 12 healthy donors were matured using IRX-2 or a mix of TNF-α, IL-1β and IL-6 (“conv. mix”). Multicolor flow cytometry was used to study the DC phenotype and antigen processing machinery (APM) component expression. ELISPOT and cytotoxicity assays were used to evaluate tumor-reactive cytotoxic T lymphocytes (CTL). IL-12p70 and IL-10 production by DC was measured by Luminex? and DC migration toward CCL21 was tested in transwell migration assays. IRX-2-matured DC functions were compared with those of conv. mix-matured DC. IRX-2-matured DC expressed higher levels (p<0.05) of CD11c, CD40, CCR7 as well as LMP2, TAP1, TAP2 and tapasin than conv. mix-matured DC. IRX-2-matured DC migrated significantly better towards CCL21, produced more IL-12p70 and had a higher IL12p70/IL-10 ratio than conv. mix-matured DC (p<0.05 for all). IRX-2-matured DC carried a higher density of tumor antigen-derived peptides, and CTL primed with these DC mediated higher cytotoxicity against tumor targets (p<0.05) compared to the conv. mix-matured DC. Conclusion Excellent ability of IRX-2 to induce ex vivo DC maturation in HNSCC patients explains, in part, its clinical benefits and emphasizes its utility in ex vivo maturation of DC generated for therapy.
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.
Triggering DTH and CTL Activity by fd Filamentous Bacteriophages: Role of CD4+ T Cells in Memory Responses
Giovanna Del Pozzo,Dina Mascolo,Rossella Sartorius,Alessandra Citro,Pasquale Barba,Luciana D'Apice,Piergiuseppe De Berardinis
Journal of Biomedicine and Biotechnology , 2010, DOI: 10.1155/2010/894971
Abstract: The ability of fd bacteriophage particles to trigger different arms of the immune system has been previously shown by us with particular emphasis on the ability of phages to raise CTL responses in vitro and in vivo. Here we show that fd virions in the absence of adjuvants are able to evoke a DTH reaction mediated by antigen specific CD8
Generation of functional CD8+ T Cells by human dendritic cells expressing glypican-3 epitopes
James O'Beirne, Farzin Farzaneh, Phillip M Harrison
Journal of Experimental & Clinical Cancer Research , 2010, DOI: 10.1186/1756-9966-29-48
Abstract: Dendritic cells (DC) were derived from adherent PBMC cultured at 37°C for 7 days in X-Vivo, 1% autologous plasma, and 800 u/ml GM-CSF plus 500 u/ml IL-4. Immature DC were transfected with 20 μg of in vitro synthesised GPC-3 mRNA by electroporation using the Easy-ject plus system (Equibio, UK) (300 V, 150 μF and 4 ms pulse time), or pulsed with peptide, and subsequently matured with lipopolysaccharide (LPS). Six predicted GPC-3 peptide epitopes were synthesized using standard f-moc technology and tested for their binding affinity to HLA-A2.1 molecules using the cell line T2.DC transfected with GPC-3 mRNA but not control DC demonstrated strong intracellular staining for GPC-3 and in vitro generated interferon-gamma expressing T cells from autologous PBMC harvested from normal subjects. One peptide, GPC-3522-530 FLAELAYDL, fulfilled our criteria as a naturally processed, HLA-A2-restricted cytotoxic T lymphocyte (CTL) epitope: i) it showed high affinity binding to HLA-A2, in T2 cell binding assay; ii) it was generated by the MHC class I processing pathway in DC transfected with GPC-3 mRNA, and iii) HLA-A2 positive DC loaded with the peptide stimulated proliferation in autologous T cells and generated CTL that lysed HLA-A2 and GPC-3 positive target cells.These findings demonstrate that electroporation of GPC-3 mRNA is an efficient method to load human monocyte-derived DC with antigen because in vitro they generated GPC-3-reactive T cells that were functional, as shown by interferon-gamma production. Furthermore, this study identified a novel naturally processed, HLA-A2-restricted CTL epitope, GPC-3522-530 FLAELAYDL, which can be used to monitor HLA-A2-restricted CTL responses in patients with HCC. Further studies are required to investigate whether anti-GPC-3 immunotherapy has a role in the treatment of GPC-3 dependent tumours, such as HCC.Increasing evidence suggests that immune responses play an important role in the control of cancer and manipulation of the immune sys
Regulatory B Cells Inhibit Cytotoxic T Lymphocyte (CTL) Activity and Elimination of Infected CD4 T Cells after In Vitro Reactivation of HIV Latent Reservoirs  [PDF]
Basile Siewe, Jennillee Wallace, Sonya Rygielski, Jack T. Stapleton, Jeffrey Martin, Steven G. Deeks, Alan Landay
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0092934
Abstract: During HIV infection, IL-10/IL-10 receptor and programmed death-1 (PD-1)/programmed death-1-ligand (PD-L1) interactions have been implicated in the impairment of cytotoxic T lymphocyte (CTL) activity. Despite antiretroviral therapy (ART), attenuated anti-HIV CTL functions present a major hurdle towards curative measures requiring viral eradication. Therefore, deeper understanding of the mechanisms underlying impaired CTL is crucial before HIV viral eradication is viable. The generation of robust CTL activity necessitates interactions between antigen-presenting cells (APC), CD4+ and CD8+ T cells. We have shown that in vitro, IL-10hiPD-L1hi regulatory B cells (Bregs) directly attenuate HIV-specific CD8+-mediated CTL activity. Bregs also modulate APC and CD4+ T cell function; herein we characterize the Breg compartment in uninfected (HIVNEG), HIV-infected “elite controllers” (HIVEC), ART-treated (HIVART), and viremic (HIVvir), subjects, and in vitro, assess the impact of Bregs on anti-HIV CTL generation and activity after reactivation of HIV latent reservoirs using suberoylanilide hydroxamic acid (SAHA). We find that Bregs from HIVEC and HIVART subjects exhibit comparable IL-10 expression levels significantly higher than HIVNEG subjects, but significantly lower than HIVVIR subjects. Bregs from HIVEC and HIVART subjects exhibit comparable PD-L1 expression, significantly higher than in HIVVIR and HIVNEG subjects. SAHA-treated Breg-depleted PBMC from HIVEC and HIVART subjects, displayed enhanced CD4+ T-cell proliferation, significant upregulation of antigen-presentation molecules, increased frequency of CD107a+ and HIV-specific CD8+ T cells, associated with efficient elimination of infected CD4+ T cells, and reduction in integrated viral DNA. Finally, IL-10-R and PD-1 antibody blockade partially reversed Breg-mediated inhibition of CD4+ T-cell proliferation. Our data suggest that, possibly, via an IL-10 and PD-L1 synergistic mechanism; Bregs likely inhibit APC function and CD4+ T-cell proliferation, leading to anti-HIV CTL attenuation, hindering viral eradication.
Impaired Functionality of Antiviral T Cells in G-CSF Mobilized Stem Cell Donors: Implications for the Selection of CTL Donor  [PDF]
Carola E. Bunse, Sylvia Borchers, Pavankumar R. Varanasi, Sabine Tischer, Constan?a Figueiredo, Stephan Immenschuh, Ulrich Kalinke, Ulrike K?hl, Lilia Goudeva, Britta Maecker-Kolhoff, Arnold Ganser, Rainer Blasczyk, Eva M. Weissinger, Britta Eiz-Vesper
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0077925
Abstract: Adoptive transfer of antiviral T cells enhances immune reconstitution and decreases infectious complications after stem cell transplantation. Information on number and function of antiviral T cells in stem cell grafts is scarce. We investigated (1) immunomodulatory effects of G-CSF on antiviral T cells, (2) the influence of apheresis, and (3) the optimal time point to collect antiviral cells. CMV-, EBV- and ADV-specific T cells were enumerated in 170 G-CSF-mobilized stem cell and 24 non-mobilized platelet donors using 14 HLA-matched multimers. T-cell function was evaluated by IFN-γ ELISpot and granzyme B secretion. Immunophenotyping was performed by multicolor flow cytometry. G-CSF treatment did not significantly influence frequency of antiviral T cells nor their in vitro expansion rate upon antigen restimulation. However, T-cell function was significantly impaired, as expressed by a mean reduction in secretion of IFN-γ (75% in vivo, 40% in vitro) and granzyme B (32% target-independent, 76% target-dependent) as well as CD107a expression (27%). Clinical follow up data indicate that the first CMV-reactivation in patients and with it the need for T-cell transfer occurs while the donor is still under the influence of G-CSF. To overcome these limitations, T-cell banking before mobilization or recruitment of third party donors might be an option to optimize T-cell production.
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.
CD154 and IL-2 Signaling of CD4+ T Cells Play a Critical Role in Multiple Phases of CD8+ CTL Responses Following Adenovirus Vaccination  [PDF]
Channakeshava Sokke Umeshappa, Roopa Hebbandi Nanjundappa, Yufeng Xie, Andrew Freywald, Yulin Deng, Hong Ma, Jim Xiang
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0047004
Abstract: Adenoviral (AdV) vectors represent most commonly utilized viral vaccines in clinical studies. While the role of CD8+ cytotoxic T lymphocyte (CTL) responses in mediating AdV-induced protection is well understood, the involvement of CD4+ T cell-provided signals in the development of functional CD8+ CTL responses remain unclear. To explore CD4+ T helper signals required for AdVova-stimulated CTL responses, we established an adoptive transfer system by transferring CD4+ T cells derived from various knock out and transgenic mice into wild-type and/or CD4-deficient animals, followed by immunizing with recombinant ovalbumin (OVA)-expressing AdVova vector. Without CD4+ T help, both primary and memory CTL responses were greatly reduced in this model, and were associated with increased PD-1 expression. The provision of OVA-specific CD4+ T help in CD4+ T cell-deficient mice restored AdVova-induced primary CTL responses, and supported survival and recall responses of AdVova-stimulated memory CTLs. These effects were specifically mediated by CD4+ T cell-produced IL-2 and CD154 signals. Adoptive transfer of “helped” or “unhelped” effector and memory CTLs into na?ve CD4+ T cell-deficient or -sufficient mice also revealed an additional role for polyclonal CD4+ T cell environment in the survival of AdVova-stimulated CTLs, partially explaining the extension of CTL contraction phase. Finally, during recall responses, CD4+ T cell environment, particularly involving memory CD4+ T cells, greatly enhanced expansion of memory CTLs. Collectively, our data strongly suggest a critical role for CD4+ T help in multiple phases of AdV-stimulated CTL responses, and could partially explain certain failures in AdV-based immunization trials targeting malignant tumors and chronic diseases that are often associated with compromised CD4+ T cell population and function.
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