Study of CTLA-4 Regulation in Large Granular Lymphocyte Leukemia Cells and Their Normal Counterparts.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3871-3871
Author(s):  
Marcin W. Wlodarski ◽  
Megan Quimper ◽  
Lukasz Gondek ◽  
Alexander Rodriquez ◽  
Jaroslaw P. Maciejewski
Keyword(s):  
Rheumatoid Arthritis ◽  
T Cell ◽  
Autoimmune Diseases ◽  
T Cell Activation ◽  
Cell Activation ◽  
T Cell Responses ◽  
Large Granular Lymphocyte ◽  
Snp Analysis ◽  
Cd8 Cells ◽  
Cell Responses

Abstract T cell large granular lymphocyte (T-LGL) leukemia is a clonal lymphoproliferation of terminal cytotoxic T cells. T-LGL differs from other lymphoid malignancies as it is not entirely autonomous but appears to be sustained by a persistent antigenic drive. The antigen driven process may be suspected based on the frequent association of T-LGL with autoimmune conditions such as autoimmune neutropenia or rheumatoid arthritis. In these diseases, the LGL clone may be a part of an initially polyclonal immune response. CTLA-4 (CD152) is an accessory molecule expressed on CD4+ and some CD8+ cells involved in the regulation of T cell responses; upon triggering by one of its ligands (B7, CD28) CTLA-4 decreases T-cell activation and proliferation and contributes to the termination of antigenic responses. Knockout CTLA-4 mice develop autoimmune symptoms and a lymphoproliferative syndrome. Clinically, CTLA-4 was implicated in the induction of allo-tolerance and in the pathophysiologic mechanisms leading to autoimmune diseases such as thyroditis and rheumatoid arthritis. In addition, polymorphisms within CTLA-4 promoter and exon I have been recognized as immunogenetic predisposition factors for a variety of autoimmune diseases. Some experimental observations suggest defective regulation of the LGL clone and various intra- and extra-cellular mechanisms were implicated. Based on the biologic properties of CTLA4, we designed our experiments to test the potential role of CTLA-4 in dysregulation of clonal T cell responses in T-LGL. Decreased expression and impaired functional activity may be a result of a genetic predisposition due to known CTLA4 promoter and exon I polymorphism, 28 LGL patients were studied using SNP analysis. We have found for the +49 A/G polymorphism in exon I that 42% of LGL patients were homozygous while 38% and 20% were heterozygous for A/G exchange and homozygous for G, respectively. However, this result was comparable to large cohorts of controls reported in various publications and controls (N=18) studied in our laboratory. No patients with CTLA-4 promoter polymorphisms (-658C>T, -319C>T) were found in the LGL cohort. Using intracellular staining and flow cytometry we studied induced and steady state expression of CD152 in LGL cells. As compared to controls (N=14) in whom PMA/Ionomycin and PHA treatment resulted in an up-modulation of the CD152 expression in CD8+ cells (3.2+/− 3.4% vs. 17+/− 6.8% upon stimulation), the inducibility of CTLA-4 was decreased in CD8+ cells derived from patients with LGL (N=11; 3.7+/− 3.5% vs. 8.2+/− 7.5% upon stimulation). Stimulation appeared to be adequate as indicated by comparable CD69 upregulation. As LGL cells phenotypically correspond to mature effector CTL, we investigated whether impaired CTLA-4 induction is rather a feature of normal mature CTL effectors rather than a defect of LGL clone. Following stimulation, we have differentially stained CD8+CD57+ and CD8+CD57− cells from controls and determined expression of CD152; mature CD57+CD8 positive cells failed to express CTLA4 upon stimulation. In analogy, similar procedure was applied to patients with LGL: normal polyclonal CD8+CD57− cells showed induction of CTLA-4 while LGL cells were refractory. These results suggest that the survival and activation of terminal effector CTL including LGL cells are not regulated by CTLA-4 expression.

Selective protein kinase Cθ (PKCθ) inhibitors for the treatment of autoimmune diseases

2014 ◽  
Vol 42 (6) ◽  
pp. 1524-1528 ◽  
Author(s):  
Adam Curnock ◽  
Clare Bolton ◽  
Peter Chiu ◽  
Elisabeth Doyle ◽  
Damien Fraysse ◽  
...  
Keyword(s):  
T Cell ◽  
Protein Kinase ◽  
Autoimmune Diseases ◽  
T Cell Activation ◽  
Cell Activation ◽  
Critical Role ◽  
T Cell Responses ◽  
Cell Responses ◽  
Viral Responses ◽  
Deficient Mice

Protein kinase Cθ (PKCθ) is a member of a large family of serine/threonine kinases that are involved in diverse cellular functions. PKCθ has roles in T-cell activation and survival, where the dependency of T-cell responses on this enzyme appears to be dictated by both the nature of the antigen and by the inflammatory environment. Studies in PKCθ-deficient mice have demonstrated that although anti-viral responses are PKCθ-independent, T-cell responses associated with autoimmune diseases are PKCθ-dependent. PKCθ-deficient mice are either resistant to or show markedly reduced symptoms in models of MS (multiple sclerosis), IBD (inflammatory bowel disease), arthritis and asthma. Thus potent and selective inhibition of PKCθ has the potential to block T-cell-mediated autoimmunity without compromising anti-viral responses. The present review describes the design and optimization of potent and selective PKCθ inhibitors and their efficacy in both in vitro and in vivo studies. First, our compounds confirm the critical role for PKCθ in T-cell activation and proliferation and secondly they help to demonstrate that murine and human memory T-cell function continues to be dependent on this enzyme. In addition, these inhibitors demonstrate impressive efficacy in treating established autoimmune disease in murine models of IBD and MS.

scholarly journals Maintenance of Viral Suppression in Human Immunodeficiency Virus Controllers Despite Waning T-Cell Responses During Antiretroviral Therapy

2020 ◽  
Vol 222 (11) ◽  
pp. 1837-1842 ◽  
Author(s):  
Nikolaus Jilg ◽  
Pilar Garcia-Broncano ◽  
Michael Peluso ◽  
Florencia P Segal ◽  
Ronald J Bosch ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cell ◽  
Antiretroviral Therapy ◽  
T Cell Activation ◽  
Cell Activation ◽  
T Cell Responses ◽  
Cell Responses ◽  
Immunodeficiency Virus ◽  
Undetectable Viremia ◽  
Hiv Controllers

Abstract AIDS Clinical Trials Group study A5308 found reduced T-cell activation and exhaustion in human immunodeficiency virus (HIV) controllers start antiretroviral therapy (ART). We further assessed HIV-specific T-cell responses and post-ART viral loads. Before ART, the 31% of participants with persistently undetectable viremia had more robust HIV-specific T-cell responses. During ART, significant decreases were observed in a broad range of T-cell responses. Eight controllers in A5308 and the Study of the Consequences of the Protease Inhibitor Era (SCOPE) cohort showed no viremia above the level of quantification in the first 12 weeks after ART discontinuation. ART significantly reduced HIV-specific T-cell responses in HIV controllers but did not adversely affect controller status after ART discontinuation.

scholarly journals Monkeypox virus evades antiviral CD4+ and CD8+ T cell responses by suppressing cognate T cell activation

2008 ◽  
Vol 105 (38) ◽  
pp. 14567-14572 ◽  
Author(s):  
E. Hammarlund ◽  
A. Dasgupta ◽  
C. Pinilla ◽  
P. Norori ◽  
K. Fruh ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
T Cell Responses ◽  
Cd8 T Cell ◽  
Monkeypox Virus ◽  
Cell Responses

scholarly journals High Frequencies of Functional Virus-Specific CD4+ T Cells in SARS-CoV-2 Subjects With Olfactory and Taste Disorders

2021 ◽  
Vol 12 ◽  
Author(s):  
Dalila Mele ◽  
Anna Calastri ◽  
Eugenia Maiorano ◽  
Antonella Cerino ◽  
Michele Sachs ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
T Cell Responses ◽  
Control Group ◽  
Presenting Symptoms ◽  
Cell Responses ◽  
Taste Disorders ◽  
Specific Igg

Olfactory and taste disorders (OTD) are commonly found as presenting symptoms of SARS-CoV-2 infection in patients with clinically mild COVID-19. Virus-specific T cells are thought to play an important role in the clearance of SARS-CoV-2; therefore the study of T cell specific immune responses in patients with mild symptoms may help to understand their possible role in protection from severe disease. We evaluated SARS-CoV-2-specific T cell responses to four different peptide megapools covering all SARS-CoV-2 proteins during the acute phase of the disease in 33 individuals with mild or no other symptom beside OTD and in 22 age-matched patients with severe infection. A control group of 15 outpatients with OTD and consistently negative nasopharyngeal SARS-CoV-2 RNA swabs and virus-specific IgG serology was included in the study. Increased frequencies of virus-specific CD4+ and CD8+ T cells were found in SARS-CoV-2 positive patients with OTD compared with those with severe COVID-19 and with SARS-CoV-2 negative OTD individuals. Moreover, enhanced CD4+ and CD8+ T-cell activation induced by SARS-CoV-2 peptides was associated with higher interferon (IFN)γ production. Increased frequencies of Spike (S1/S2)-specific CD4+ T cells showing enhanced IFNγ secretion and granzyme B content were associated with serum spike-specific IgG in the OTD group. In conclusion, patients with SARS-CoV-2 induced OTD develop highly functional virus-specific CD4+ and CD8+ T cells during the symptomatic phase of the disease, suggesting that robust and coordinated T-cell responses provide protection against extension of COVID-19 to the lower respiratory tract.

Abstract 449: Novel Role of Bim in the Regulation of Allogeneic T-Cell Activation and Development of Transplant Vasculopathy

2012 ◽  
Vol 32 (suppl_1) ◽  
Author(s):  
Anna von Rossum ◽  
Winnie Enns ◽  
Yu P Shi ◽  
Jonathan C Choy
Keyword(s):  
T Cells ◽  
Cell Death ◽  
T Cell ◽  
T Cell Activation ◽  
Cd8 T Cells ◽  
Cell Activation ◽  
T Cell Responses ◽  
Intimal Thickening ◽  
Cell Responses ◽  
Transplant Vasculopathy

Transplant vasculopathy (TV) is an arteriosclerotic disease characterized by intimal thickening of allograft arteries and is a leading cause of heart transplant rejection. T cell responses towards allograft arteries are responsible for the development of TV and understanding the regulatory pathways controlling T cell activation in allograft arteries provides opportunities for the therapeutic attenuation of TV as well as other arteriosclerotic diseases. Bim is a pro-apoptotic Bcl-2 protein known to down-regulate immune responses after viral infections by inducing cell death of effector T cells but its role in regulating allogeneic T cell responses is not known. We compared cell death and alloantigen-driven activation of T cells from Bim +/+ (wild-type), Bim +/- and Bim -/- mice as well as the development of TV in these mice. Bim was required for cell death of both CD4 and CD8 T cells in response to cytokine deprivation in vitro . Unexpectedly, Bim was also required for alloantigen-induced proliferation of both CD4 and CD8 T cells as well as for IL-2 production. When TV was examined in aortic interposition grafts implanted into complete major histocompatibility complex-mismatched mice, intimal thickening was significantly reduced in Bim +/- but not Bim -/- recipients as compared to Bim +/+ counterparts. There was signficantly less CD4 T cell accumulation in the intima of arteries from Bim +/- as compared to Bim +/+ recipients but this effect was not observed in Bim -/- recipients. The accumulation of CD8 T cells in allograft arteries was not affected by differences in Bim expression. Taken together, our data support a novel role for Bim in driving T cell activation in response to allogeneic stimuli and indicate that the effects of this Bcl-2 protein in the pathogenesis of TV likely depends on its dual role in supporting T cell activation and death.

scholarly journals Vector Order Determines Protection against Pathogenic Simian Immunodeficiency Virus Infection in a Triple-Component Vaccine by Balancing CD4+ and CD8+ T-Cell Responses

2017 ◽  
Vol 91 (23) ◽  
Author(s):  
Ulrike Sauermann ◽  
Antonia Radaelli ◽  
Nicole Stolte-Leeb ◽  
Katharina Raue ◽  
Massimiliano Bissa ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Responses ◽  
T Cell Activation ◽  
Cell Activation ◽  
T Cell Responses ◽  
Target Cells ◽  
Aids Vaccine ◽  
Cell Responses ◽  
Antibody Titers

ABSTRACT An effective AIDS vaccine should elicit strong humoral and cellular immune responses while maintaining low levels of CD4+ T-cell activation to avoid the generation of target cells for viral infection. The present study investigated two prime-boost regimens, both starting vaccination with single-cycle immunodeficiency virus, followed by two mucosal boosts with either recombinant adenovirus (rAd) or fowlpox virus (rFWPV) expressing SIVmac239 or SIVmac251 gag/pol and env genes, respectively. Finally, vectors were switched and systemically administered to the reciprocal group of animals. Only mucosal rFWPV immunizations followed by systemic rAd boost significantly protected animals against a repeated low-dose intrarectal challenge with pathogenic SIVmac251, resulting in a vaccine efficacy (i.e., risk reduction per exposure) of 68%. Delayed viral acquisition was associated with higher levels of activated CD8+ T cells and Gag-specific gamma interferon (IFN-γ)-secreting CD8+ cells, low virus-specific CD4+ T-cell responses, and low Env antibody titers. In contrast, the systemic rFWPV boost induced strong virus-specific CD4+ T-cell activity. rAd and rFWPV also induced differential patterns of the innate immune responses, thereby possibly shaping the specific immunity. Plasma CXCL10 levels after final immunization correlated directly with virus-specific CD4+ T-cell responses and inversely with the number of exposures to infection. Also, the percentage of activated CD69+ CD8+ T cells correlated with the number of exposures to infection. Differential stimulation of the immune response likely provided the basis for the diverging levels of protection afforded by the vaccine regimen. IMPORTANCE A failed phase II AIDS vaccine trial led to the hypothesis that CD4+ T-cell activation can abrogate any potentially protective effects delivered by vaccination or promote acquisition of the virus because CD4+ T helper cells, required for an effective immune response, also represent the target cells for viral infection. We compared two vaccination protocols that elicited similar levels of Gag-specific immune responses in rhesus macaques. Only the animal group that had a low level of virus-specific CD4+ T cells in combination with high levels of activated CD8+ T cells was significantly protected from infection. Notably, protection was achieved despite the lack of appreciable Env antibody titers. Moreover, we show that both the vector and the route of immunization affected the level of CD4+ T-cell responses. Thus, mucosal immunization with FWPV-based vaccines should be considered a potent prime in prime-boost vaccination protocols.

scholarly journals Specific interaction of lymphocyte function-associated antigen 3 with CD2 can inhibit T cell responses.

1993 ◽  
Vol 178 (1) ◽  
pp. 211-222 ◽  
Author(s):  
G T Miller ◽  
P S Hochman ◽  
W Meier ◽  
R Tizard ◽  
S A Bixler ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Surface ◽  
T Cell Activation ◽  
Cell Activation ◽  
Hepatitis B Surface Antigen ◽  
Specific Interaction ◽  
T Cell Responses ◽  
Accessory Cell ◽  
Lymphocyte Function ◽  
Cell Responses

Accessory cell surface molecules, such as T cell antigen CD2 and its ligand lymphocyte function-associated antigen 3 (LFA-3; CD58), are critical costimulatory pathways for optimal T cell activation in response to antigens. Interaction of CD2 with cell surface LFA-3 not only increases T cell/accessory cell adhesion, but also induces signal transduction events involved in the regulation of T cell responses. In this report, we show that specific interactions of LFA-3 with CD2 can result in T cell unresponsiveness to antigenic or mitogenic stimuli in vitro. By deletion of certain regions of the extracellular domain of LFA-3, we localized the CD2 binding site to the first domain of LFA-3. We then demonstrated that a soluble, purified first domain-LFA-3/IgG1 fusion protein (LFA3TIP) interacts with CD2 and binds to the same CD2 epitope as purified multimeric or cell surface-expressed LFA-3. LFA3TIP inhibits tetanus toxoid, hepatitis B surface antigen, anti-CD3 mAb, Con A, and phytohemagglutinin P-induced T cell proliferation, as well as xenogeneic and allogeneic mixed lymphocyte reactions (MLR). Unlike anti-LFA-3 or anti-CD2 monoclonal antibodies (mAbs) which inhibit T cell responses by blocking LFA-3/CD2 binding, LFA3TIP is capable of rendering T cells unresponsive to antigenic stimuli in situations where T cell activation is independent of CD2/LFA-3 interactions. Furthermore, LFA3TIP, but not blocking anti-CD2 mAbs, is capable of inducing T cell unresponsiveness to secondary stimulation in allogeneic MLR. This inhibition of T cell responses by LFA3TIP occurs through a different mechanism from that of mAbs to LFA-3 or CD2.

scholarly journals Virus-based vaccine vectors with distinct replication mechanisms differentially infect and activate dendritic cells

npj Vaccines ◽  
2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Carolina Chiale ◽  
Anthony M. Marchese ◽  
Yoichi Furuya ◽  
Michael D. Robek
Keyword(s):  
Dendritic Cells ◽  
T Cell ◽  
Virus Replication ◽  
T Cell Activation ◽  
Viral Vectors ◽  
Cell Activation ◽  
T Cell Responses ◽  
Cell Responses ◽  
Identical Cell

AbstractThe precise mechanism by which many virus-based vectors activate immune responses remains unknown. Dendritic cells (DCs) play key roles in priming T cell responses and controlling virus replication, but their functions in generating protective immunity following vaccination with viral vectors are not always well understood. We hypothesized that highly immunogenic viral vectors with identical cell entry pathways but unique replication mechanisms differentially infect and activate DCs to promote antigen presentation and activation of distinctive antigen-specific T cell responses. To evaluate differences in replication mechanisms, we utilized a rhabdovirus vector (vesicular stomatitis virus; VSV) and an alphavirus-rhabdovirus hybrid vector (virus-like vesicles; VLV), which replicates like an alphavirus but enters the cell via the VSV glycoprotein. We found that while virus replication promotes CD8+ T cell activation by VLV, replication is absolutely required for VSV-induced responses. DC subtypes were differentially infected in vitro with VSV and VLV, and displayed differences in activation following infection that were dependent on vector replication but were independent of interferon receptor signaling. Additionally, the ability of the alphavirus-based vector to generate functional CD8+ T cells in the absence of replication relied on cDC1 cells. These results highlight the differential activation of DCs following infection with unique viral vectors and indicate potentially discrete roles of DC subtypes in activating the immune response following immunization with vectors that have distinct replication mechanisms.

scholarly journals Visualising the interaction of CD4 T cells and DCs in the evolution of inflammatory arthritis

2018 ◽  
Vol 77 (4) ◽  
pp. 579-588 ◽  
Author(s):  
Catriona T Prendergast ◽  
Agapitos Patakas ◽  
Shaima Al-Khabouri ◽  
Claire L McIntyre ◽  
Iain B McInnes ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
T Cell Responses ◽  
Receptor Expression ◽  
Phenotypic Analysis ◽  
Necrosis Factor Alpha ◽  
Cell Responses

ObjectivesSuccessful early intervention in rheumatoid arthritis (RA) with the aim of resetting immunological tolerance requires a clearer understanding of how specificity, cellular kinetics and spatial behaviour shape the evolution of articular T cell responses. We aimed to define initial seeding of articular CD4+ T cell responses in early experimental arthritis, evaluating their dynamic behaviour and interactions with dendritic cells (DCs) in the inflamed articular environment.MethodsAntigen-induced arthritis was used to model articular inflammation. Flow cytometry and PCR of T cell receptor (TCR) diversity genes allowed phenotypic analysis of infiltrating T cells. The dynamic interactions of T cells with joint residing DCs were visualised using intravital multiphoton microscopy.ResultsInitial recruitment of antigen-specific T cells into the joint was paralleled by accumulation of CD4+ T cells with diverse antigen-receptor expression and ability to produce tumour necrosis factor alpha (TNFα) and interferon gamma (IFNγ) on mitogenic restimulation. A proportion of this infiltrate demonstrated slower motility speeds and engaged for longer periods with articular DCs in vivo. Abatacept treatment did not disrupt these interactions but did reduce T cell expression of inducible costimulatory (ICOS) molecule. We also demonstrated that non-specific CD4+ T cells could be recruited during these early articular events.ConclusionsWe demonstrate that CD4+ T cells engage with articular DCs supporting antigen specific T cell reactivation. This cellular dialogue can be targeted therapeutically to reduce local T cell activation.

Restriction of PD-1 function by cis-PD-L1/CD80 interactions is required for optimal T cell responses

Science ◽  
2019 ◽  
Vol 364 (6440) ◽  
pp. 558-566 ◽  
Author(s):  
Daisuke Sugiura ◽  
Takumi Maruhashi ◽  
Il-mi Okazaki ◽  
Kenji Shimizu ◽  
Takeo K. Maeda ◽  
...  
Keyword(s):  
T Cell ◽  
Immune Responses ◽  
T Cell Activation ◽  
Cell Activation ◽  
Checkpoint Inhibitors ◽  
T Cell Responses ◽  
Cell Responses ◽  
Critical Components ◽  
Antigen Presenting ◽  
In Cis

Targeted blockade of PD-1 with immune checkpoint inhibitors can activate T cells to destroy tumors. PD-1 is believed to function mainly at the effector, but not in the activation, phase of T cell responses, yet how PD-1 function is restricted at the activation stage is currently unknown. Here we demonstrate that CD80 interacts with PD-L1 in cis on antigen-presenting cells (APCs) to disrupt PD-L1/PD-1 binding. Subsequently, PD-L1 cannot engage PD-1 to inhibit T cell activation when APCs express substantial amounts of CD80. In knock-in mice in which cis-PD-L1/CD80 interactions do not occur, tumor immunity and autoimmune responses were greatly attenuated by PD-1. These findings indicate that CD80 on APCs limits the PD-1 coinhibitory signal, while promoting CD28-mediated costimulation, and highlight critical components for induction of optimal immune responses.

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