scholarly journals The Level of Viral Antigen Presented by Hepatocytes Influences CD8 T-Cell Function

2007 ◽  
Vol 81 (6) ◽  
pp. 2940-2949 ◽  
Author(s):  
Adam J. Gehring ◽  
Dianxing Sun ◽  
Patrick T. F. Kennedy ◽  
Esther Nolte-'t Hoen ◽  
Seng Gee Lim ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Viral Antigen ◽  
Cell Function ◽  
Cd8 T Cell ◽  
T Cell Function ◽  
Tnf Α ◽  
Antiviral Function ◽  
Ifn Γ

ABSTRACT CD8 T cells exert their antiviral function through cytokines and lysis of infected cells. Because hepatocytes are susceptible to noncytolytic mechanisms of viral clearance, CD8 T-cell antiviral efficiency against hepatotropic viruses has been linked to their capacity to produce gamma interferon (IFN-γ) and tumor necrosis factor alpha (TNF-α). On the other hand, intrahepatic cytokine production triggers the recruitment of mononuclear cells, which sustain acute and chronic liver damage. Using virus-specific CD8 T cells and human hepatocytes, we analyzed the modulation of virus-specific CD8 T-cell function after recognition peptide-pulsed or virally infected hepatocytes. We observed that hepatocyte antigen presentation was generally inefficient, and the quantity of viral antigen strongly influenced CD8 T-cell antiviral function. High levels of hepatitis B virus production induced robust IFN-γ and TNF-α production in virus-specific CD8 T cells, while limiting amounts of viral antigen, both in hepatocyte-like cells and naturally infected human hepatocytes, preferentially stimulated CD8 T-cell degranulation. Our data document a mechanism where virus-specific CD8 T-cell function is influenced by the quantity of virus produced within hepatocytes.

Histone Deacetylase 11 (HDAC11) Regulates Cytotoxic T-Cell Function and Memory Phenotype

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 840-840
Author(s):  
David M Woods ◽  
Karrune V. Woan ◽  
Eva Sahakian ◽  
John Powers ◽  
Fengdong Cheng ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Cell Function ◽  
Cd8 T Cell ◽  
Central Memory ◽  
Negative Regulator ◽  
Wild Type ◽  
Potential Target ◽  
T Cell Function

Abstract Abstract 840 T-cells are an essential component of immune mediated tumor rejection. Adoptive transfer of T-cells results in a durable anti-tumor response in some patients with hematological malignancies. To further improve the efficacy of T-cell adoptive transfers, a better understanding of the regulatory checkpoints of these cells is needed. Here we show that HDAC11 is a negative regulator of CD8+ T-cell function, thus representing a potential target in adoptive immunotherapy. HDACs are a group of enzymes initially known for their role in deacetylating histones, thereby condensing chromatin structure and repressing gene expression. The known roles of HDACs as epigenetic regulators have recently expanded to include more complex regulatory functions including interactions with non-histone targets. HDAC11 is the most recently identified member of the HDAC family, and is highly expressed in brain, testis and T-cells. Recently, our group reported HDAC11 as a regulator of IL-10 production in antigen presenting cells. To determine the role of HDAC11 in T-cell biology, T-cells from HDAC11 knock out (HDAC11KO) mice were compared to wild-type T-cells in number, function and phenotype. HDAC11KO T-cells had no differences in absolute number or percentages of CD4+ or CD8+ lymphocytes. However CD8+ T-cells were hyper-proliferative upon CD3/CD28 stimulation and produced significantly higher levels of the pro-inflammatory, Tc1 cytokines IL-2, INF-γ, and TNF-α. However, no significant increases in the production of the Tc2 cytokines IL-4, IL-6 or IL-10 were seen. Further investigation of phenotypic differences also revealed that HDAC11KO mice have a larger percentage of central memory CD8+ T-cells. Additionally, HDAC11KO CD8+ T-cells express higher levels of the transcription factor Eomes, a known contributor to central memory cell formation as well as a controller of granzyme B and perforin production in CD8+ T-cells. This Tc1 and central memory-like phenotype translated to delayed tumor progression and survival in vivo in C1498 AML bearing mice treated with adoptively transferred HDAC11KO T-cells, as compared with wild type T-cells. Collectively, we have demonstrated HDAC11 as a negative regulator of CD8+ T-cell function, and a novel potential target to augment the efficacy of adoptive T-cell tumor immunotherapy. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Combination rhIL-15 and Anti-PD-L1 (Avelumab) Enhances HIVGag-Specific CD8 T-Cell Function

2020 ◽  
Vol 222 (9) ◽  
pp. 1540-1549
Author(s):  
Bruktawit A Goshu ◽  
Hui Chen ◽  
Maha Moussa ◽  
Jie Cheng ◽  
Marta Catalfamo
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Cell Function ◽  
Cd8 T Cell ◽  
Peripheral Tissues ◽  
T Cell Function ◽  
Interleukin 15 ◽  
Checkpoint Receptors

Abstract In chronic HIV infection, virus-specific cytotoxic CD8 T cells showed expression of checkpoint receptors and impaired function. Therefore, restoration of CD8 T-cell function is critical in cure strategies. Here, we show that in vitro blockade of programmed cell death ligand 1 (PD-L1) by an anti-PD-L1 antibody (avelumab) in combination with recombinant human interleukin-15 (rhIL-15) synergistically enhanced cytokine secretion by proliferating HIVGag-specific CD8 T cells. In addition, these CD8 T cells have a CXCR3+PD1−/low phenotype, suggesting a potential to traffic into peripheral tissues. In vitro, proliferating CD8 T cells express PD-L1 suggesting that anti-PD-L1 treatment also targets virus-specific CD8 T cells. Together, these data indicate that rhIL-15/avelumab combination therapy could be a useful strategy to enhance CD8 T-cell function in cure strategies.

Impact of Donor Serostatus on CMV Reactivation and Reconstitution of Multi-Function CMV-Specific T Cells in CMV-Positive Transplant Recipients

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4339-4339
Author(s):  
Wendi Zhou ◽  
Jeff Longmate ◽  
Simon F Lacey ◽  
Joycelynne Palmer ◽  
Ghislaine Gallez-Hawkins ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
T Cell ◽  
Cd8 T Cells ◽  
Cd8 T Cell ◽  
Donor Group ◽  
Functional Profile ◽  
Tnf Α ◽  
Ifn Γ ◽  
Cmv Reactivation

Abstract CMV reactivation remains a significant cause of morbidity and mortality due to the extended period of immunodeficiency after allogeneic hematopoietic stem cell transplantation (HCT), despite great strides in management of the infection in the past two decades. Reconstitution of cytomegalovirus (CMV)-specific CD8+ T cells is essential to control of CMV infection in CMV-seropositive recipients (R+) after HCT. The CMV serologic status of the recipient before HCT has a strong influence on outcome. Key questions addressed in this study are the impact of donor CMV serostatus on the reconstitution of effective CMV immunity or risk of CMV reactivation and GCV usage in CMV R+ recipients. Betts and colleagues have reported that HIV-specific CD8+ T-cells which simultaneously degranulated and produced IFN-γ, TNF-α, MIP-1β and IL2 were associated with lower viral load and HIV long term non-progressor status. These findings in the context of HIV infection motivated us to investigate whether levels of multi-functional CMV-specific CD8+ T-cells in HCT recipients correlated with the CMV serostatus of the donor and the differentiation state of transferred CMV-specific memory T-cells. We hypothesize that a mature CD8+ T-cell functional profile leads to a lower incidence of CMV viremia in R+ recipients of T-cell replete HCT with a D+ donor. A total of 183 R+ HCT recipients were enrolled. CMV reactivation was defined as any positive CMV blood culture or plasma PCR obtained during a monitoring period that began at d40 post-HCT and continued thereafter twice weekly until d100. After d100, CMV in plasma was monitored in patients at high risk because of GVHD or immunosuppressive medication. Peripheral blood mononuclear cells from R+ HCT recipients were collected at intervals between d90 and d360 post-HCT. A subset (n=123) of the subjects limited only by sample availability were evaluated for CMV-specific CD8+ T-cells producing IFN-g (IFN-γ-CD8+). We used a well-described pp65 peptide library as a stimulatory antigen to evaluate the ex vivo functional profile of pp65-specific CD8+ T-cells from R+ recipients either receiving CMV seropositive (D+/R+) or seronegative (D−/R+) T-cell replete donor grafts. D+ status was associated with higher IFN-γ-CD8+ during the sampling time-course by fitting linear generalized estimating equation models on a logarithmic scale (p=0.0004). A significant interaction was found between prior CMV reactivation and donor serostatus on IFN-γ-CD8+ levels (p=0.0001). Comparing the subset of IFN-γ-CD8+ measurements prior to reactivation, the D− donor group produced lower levels of IFN-γ-CD8+ than the D+ donor group (p=0.0002), although both donor groups have similar levels of IFN-γ-CD8+ post-reactivation. Similar results were obtained when adjusting for the 9 pre-transplant covariates, and none were associated with IFN-γ-CD8+ levels, except donor serostatus and its interaction with CMV reactivation. Six-color flow cytometry was used to assess the functional profile of CMV-specific CD8+ T-cells in 62 of 183 HCT recipients prospectively followed for CMV reactivation. R+ recipients receiving grafts from D− donors (D−/R+) reconstituted fewer multi-functional CD8+ T-cells expressing IFN-γ, TNF-α, MIP-1β and CD107 compared to D+/R+ recipients. Unlike mono-functional CD8+ T-cells secreting IFN-g, which were abundantly generated during CMV reactivation in D−/R+, the relative lack of multi-functional CD8+ T-cells persisted until at least one year post-HCT. In addition, D−/R+ recipients had more CMV reactivation than D+/R+ recipients. D+/R+ transplants have elevated levels of multi-functional CD8+ T cell levels and lower hazard for CMV reactivation. Virologic and immunologic outcomes were robust to adjustment for pre-transplant factors affecting HCT, including donor type, stem cell source, recipient age, and preparative regimen. Statistical modeling to account for pre- and post-transplant factors including GVHD and its treatment by steroids had minimal effect on the contribution of serostatus to the risk of CMV reactivation and differences in multi-functional CD8+ T cell levels.

scholarly journals Protective Immunity against Secondary Poxvirus Infection Is Dependent on Antibody but Not on CD4 or CD8 T-Cell Function

2006 ◽  
Vol 80 (13) ◽  
pp. 6333-6338 ◽  
Author(s):  
Vijay Panchanathan ◽  
Geeta Chaudhri ◽  
Gunasegaran Karupiah
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Primary Infection ◽  
Protective Immunity ◽  
Cell Function ◽  
Secondary Infection ◽  
Cd8 T Cell ◽  
Ectromelia Virus ◽  
T Cell Function

ABSTRACT Renewed interest in smallpox and the need for safer vaccines have highlighted our lack of understanding of the requirements for protective immunity. Since smallpox has been eradicated, surrogate animal models of closely related orthopoxviruses, such as ectromelia virus, have been used to establish critical roles for CD8 T cells in the control of primary infection. To study the requirements for protection against secondary infection, we have used a prime-challenge regime, in which avirulent ectromelia virus was used to prime mice that were then challenged with virulent ectromelia virus. In contrast to primary infection, T cells are not required for recovery from secondary infection, since gene knockout mice deficient in CD8 T-cell function and wild-type mice acutely depleted of CD4, CD8, or both subsets were fully protected. Protection correlated with effective virus control and generation of neutralizing antibody. Notably, primed mice that lacked B cells, major histocompatibility complex class II, or CD40 succumbed to secondary infection. Thus, antibody is essential, but CD4 or CD8 T cells are not required for recovery from secondary poxvirus infection.

scholarly journals Assessment of the Phenotype and Functionality of Porcine CD8 T Cell Responses following Vaccination with Live Attenuated Classical Swine Fever Virus (CSFV) and Virulent CSFV Challenge

2013 ◽  
Vol 20 (10) ◽  
pp. 1604-1616 ◽  
Author(s):  
Giulia Franzoni ◽  
Nitin V. Kurkure ◽  
Daniel S. Edgar ◽  
Helen E. Everett ◽  
Wilhelm Gerner ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Classical Swine Fever Virus ◽  
T Cell Responses ◽  
Classical Swine Fever ◽  
Cd8 T Cell ◽  
Cell Responses ◽  
Tnf Α ◽  
Ifn Γ

ABSTRACTVaccination with live attenuated classical swine fever virus (CSFV) induces solid protection after only 5 days, which has been associated with virus-specific T cell gamma interferon (IFN-γ) responses. In this study, we employed flow cytometry to characterize T cell responses following vaccination and subsequent challenge infections with virulent CSFV. The CD3+CD4−CD8hiT cell population was the first and major source of CSFV-specific IFN-γ. A proportion of these cells showed evidence for cytotoxicity, as evidenced by CD107a mobilization, and coexpressed tumor necrosis factor alpha (TNF-α). To assess the durability and recall of these responses, a second experiment was conducted where vaccinated animals were challenged with virulent CSFV after 5 days and again after a further 28 days. While virus-specific CD4 T cell (CD3+CD4+CD8α+) responses were detected, the dominant response was again from the CD8 T cell population, with the highest numbers of these cells being detected 14 and 7 days after the primary and secondary challenges, respectively. These CD8 T cells were further characterized as CD44hiCD62L−and expressed variable levels of CD25 and CD27, indicative of a mixed effector and effector memory phenotype. The majority of virus-specific IFN-γ+CD8 T cells isolated at the peaks of the response after each challenge displayed CD107a on their surface, and subpopulations that coexpressed TNF-α and interleukin 2 (IL-2) were identified. While it is hoped that these data will aid the rational design and/or evaluation of next-generation marker CSFV vaccines, the novel flow cytometric panels developed should also be of value in the study of porcine T cell responses to other pathogens/vaccines.

B and T Lymphocyte Attenuator (BTLA)/Herpes Virus Entry Mediator (HVEM) Interaction: Attenuating Virus Specific CD8+T Cell Function In HTLV-1 Infection

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4727-4727
Author(s):  
Ezinne Chioma Chibueze ◽  
Makoto Yoshimitsu ◽  
Naomichi Arima
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Cell Function ◽  
Virus Entry ◽  
Cd8 T Cell ◽  
Healthy Individuals ◽  
Asymptomatic Carriers ◽  
T Cell Function ◽  
Inhibitory Molecules

Background and Aims Human T-lymphotropic virus type 1(HTLV-1) infection is a retroviral infection with varied manifestations, either clinically asymptomatic carriers (AC) or symptomatic with about 1-5% developing the hematological manifestation, Adult T cell lymphoma/leukemia (ATLL). The host response to virus infections is mediated by CD8+ T cell function which in turn is partly mediated by expression of inhibitory molecules. Expression of these inhibitory molecules is a feature of dysfunctional CD8+T cells. CD8+ T cells from HTLV-1 infected individuals have been shown to be dysfunctional, in part due to expression of inhibitory molecules. One of such molecules is BTLA (B and T lymphocyte attenuator), a member of the CD28 co-signaling family of receptors. BTLA has been shown to interact with HVEM (herpes virus entry mediator) and to have varied functions on CD8+T cell function; however, its role in virus specific CD8+T cells in HTLV-1 infection has not been addressed. Methods Peripheral blood mononuclear cells (PBMCs) were isolated by Ficoll centrifugation and cryopreserved until use. For staining, cells were incubated with fluorochrome-conjugated antibodies against BTLA, CD4, CD8, and HVEM. We compared the ex-vivo expression of BTLA on CD8+ T cells (ATLL, n=14; AC, n= 9; Healthy Individuals, n=11) and virus specific CD8+T cells corresponding to prevalent immune-dominant epitopes HLA tetramers HLA-A*0201 (Tax 11-19) or *2402 (Tax 301-309) obtained from HTLV-1 infected patients (ATLL, n=6; AC, n=6). We analyzed the expression of HVEM on CD4+ T cells; to determine the effect of addition of HVEM antibodies on CD8+ T lymphocyte function, PBMCs were cultured with and without Tax peptide and/or anti-HVEM monoclonal antibody in the presence of monensin and surface degranulation of CD107a measured in in-vitro assays. Quantitation was done using FACS Calibur flow-cytometer and analyzed with Flowjo software. Differences were analyzed by Mann-Whitney U test and pairs by Wilcoxon matched pairs test using GraphPad Prism (6.01). p-values <0.05 were considered significant. Results We observed a significantly lower expression of BTLA on CD8+T cells from HTLV-1 infected (Asymptomatic carriers (AC)) and Adult T cell leukemia/lymphoma (ATLL)) compared to healthy individuals (AC =17.8 ± 4.8(mean ± standard error), n=9; ATLL= 15.9 ± 4.2, n= 14; Healthy individuals = 33.4 ± 4.9, n=9; (p ATLL: HI <0.05; AC: HI <0.05)). We also observed a down-regulation of BTLA expression on HTLV-1 specific CD8+T cells in both ATLL and asymptomatic carriers. HVEM (herpes-virus entry mediator) was also expressed on CD4+ T cells but down regulated on CD4+ T cells from ATLL in comparison to asymptomatic carriers( ATLL= 60.9 ±4.7(n=11); AC =88.3 ± 2.2 (n=12); HI= 84.07± 2.5; p ATLL: HI= <0.05). Addition of HVEM monoclonal antibodies in the presence of tax stimulation resulted in an improvement in CD8+ T cell function as measured by surface degranulation of CD107a compared to tax stimulation alone( tax stimulation(26.8 ± 4.4) : tax stimulation + HVEM antibody addition( 39.4±3.7); p< 0.05). Conclusion Our findings indicate a possible involvement of BTLA/HVEM signaling in the regulation of immune response to HTLV-1 infection and suggests an involvement in the exhaustion/attenuation of HTLV-1- specific CD8+ T cells with possible extension to therapeutic interventions in the treatment of HTLV-1 infection. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Type 1 Cytotoxic T Cells Increase in Placenta after Intrauterine Inflammation

2021 ◽  
Vol 12 ◽  
Author(s):  
Jin Liu ◽  
Yang Liu ◽  
Snigdha Panda ◽  
Anguo Liu ◽  
Jun Lei ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
T Cells ◽  
T Cell ◽  
Mouse Model ◽  
Cd8 T Cells ◽  
Cytotoxic T Cells ◽  
Cd8 T Cell ◽  
Tnf Α ◽  
Ifn Γ

CD8+ T cells recognize non-self antigen by MHC class I molecules and kill the target cells by the release of proinflammatory cytokines such as interferon gamma (IFN-γ) and tumor necrosis factor alpha (TNF-α). Our group previously reported an increase of CD8+ T‐cell trafficking in the placenta with exposure to Lipopolysaccharides (LPS). CD8+ cytotoxic T cells have been classified into distinct subsets based upon cytokine production: Tc1 cells produce IFN-γ, Tc2 cells produce interleukin 4 (IL-4). Accordingly, the purpose of this research is to analyze the subsets of placenta CD8+ T cells. We hypothesized that LPS injection would induce a change of properties of CD8+ T cell and Tc1/Tc2 ratio. We investigated the subsets of CD8+ T cell infiltration to placenta and their specific function in response to LPS-induced inflammation in a mouse model. At embryonic (E) day 17, pregnant CD-1 dams received an intrauterine injection of 25 µg LPS in100 μl PBS or 100 μl of PBS only. Flow cytometry was used to quantify CD8+ T cells, evaluate the phenotype and subtypes, and detect markers of Tc1 and Tc2 cells in placenta, at 6 hours and 24 hours post injection (hpi). Intracellular staining and flow cytometry were performed to characterize cytokines produced by CD8+ T cells. Standard statistical analysis were employed. After 6 and 24 hours of LPS injection, total CD8 T cells increased (P&lt;0.05). Tc1 cells expanded (P&lt;0.05) in LPS-treated dams compared with the PBS group. The Tc1/Tc2 ratio was significantly higher in the LPS group than the PBS group (P&lt;0.05). The expression of TNF-α and IFN-γ were increased in LPS group both at 6hpi and 24 hpi (P&lt;0.05). We identified functional placental CD8+ T cell subtypes and found a significant increase ratio of Tc1/Tc2. Following IUI, CD8+ T cells induced inflammatory response in the placenta primarily via the production of Type 1 cytokines such as IFN-γ and TNF-α. We have provided evidence of a Tc1-bias response and cytokines in the mouse model of IUI.

scholarly journals Virally Activated CD8 T Cells Home to Mycobacterium bovis BCG-Induced Granulomas but Enhance Antimycobacterial Protection Only in Immunodeficient Mice

2006 ◽  
Vol 75 (3) ◽  
pp. 1154-1166 ◽  
Author(s):  
Laura H. Hogan ◽  
Dominic O. Co ◽  
Jozsef Karman ◽  
Erika Heninger ◽  
M. Suresh ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Mycobacterium Bovis ◽  
Cd8 T Cells ◽  
Bacterial Load ◽  
Granulomatous Inflammation ◽  
Cd8 T Cell ◽  
Activated T Cells ◽  
Immunodeficient Mice ◽  
Ifn Γ

ABSTRACT The effect of secondary infections on CD4 T-cell-regulated chronic granulomatous inflammation is not well understood. Here, we have investigated the effect of an acute viral infection on the cellular composition and bacterial protection in Mycobacterium bovis strain bacille Calmette-Guérin (BCG)-induced granulomas using an immunocompetent and a partially immunodeficient murine model. Acute lymphocytic choriomeningitis virus (LCMV) coinfection of C57BL/6 mice led to substantial accumulation of gamma interferon (IFN-γ)-producing LCMV-specific T cells in liver granulomas and increased local IFN-γ. Despite traffic of activated T cells that resulted in a CD8 T-cell-dominated granuloma, the BCG liver organ load was unaltered from control levels. In OT-1 T-cell-receptor (TCR) transgenic mice, ovalbumin (OVA) immunization or LCMV coinfection of BCG-infected mice induced CD8 T-cell-dominated granulomas containing large numbers of non-BCG-specific activated T cells. The higher baseline BCG organ load in this CD8 TCR transgenic animal allowed us to demonstrate that OVA immunization and LCMV coinfection increased anti-BCG protection. The bacterial load remained substantially higher than in mice with a more complete TCR repertoire. Overall, the present study suggests that peripherally activated CD8 T cells can be recruited to chronic inflammatory sites, but their contribution to protective immunity is limited to conditions of underlying immunodeficiency.

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