More than 100 different human papillomavirus (HPV) types have been isolated so far, and they can be sub-grouped in cutaneous or mucosal according to their ability to infect the skin or the mucosa of ...the genital or upper-respiratory tracts. A sub-group of human mucosal HPVs, referred to as high-risk HPV types, is responsible for approximately 5% of all human cancers, which represents one-third of all the tumours induced by viruses. Epidemiological and biological studies have shown that HPV16 is the most oncogenic type within the high-risk group. Emerging lines of evidence suggest that, in addition to the high-risk mucosal HPV types, certain cutaneous HPVs are involved in skin cancer. HPV-associated cancers are intimately linked to HPV persistence and the accumulation of chromosomal rearrangements. The products of the early genes, E6 and E7, of the high-risk mucosal HPV types play a key role in both events. Indeed, these proteins have developed a number of strategies to evade host immuno-surveillance allowing viral persistence, and to alter cell cycle and apoptosis control, facilitating the accumulation of DNA damage/mutations. Often, the two oncoproteins target the same cellular pathways with different mechanisms, showing a strong synergism in promoting cellular transformation and neutralizing the immune response. Here, we review most of the findings on the biological properties and molecular mechanisms of the oncoproteins E6 and E7 from mucosal and cutaneous HPV types.
Abstract
According to Bloom’s taxonomy classification create, meant as the production of new and original work, represents the highest and most advanced level of cognitive domain in the learning ...process. Through creative expression students are encouraged to demonstrate their knowledge by combining elements together and by building something coherent, tangible or conceptual.
Meta-Lectureis intended as a non-traditional method to assess mastery of course concepts incorporating short lectures prepared by students, individually, in pair or in a small group, on selected topic, with emphasis on application of course content. This pedagogical approach in teaching is suitable for undergraduate introductory courses as well as for more advanced courses. It represents a student engagement method in both face-to-face and hybrid environment, that aims to improve student commitment and class participation.
Through this alternative method, by simulating a professional environment such as public speaking, poster and seminar scientific presentation, students benefit from the experience of reversed role and from instructor’s and audience feedback on the individual evaluation.
This report provides introduction to the Meta-Lectureassignment, guidance on the feedback analysis and discussion on the learning process.
Dendritic cells (DCs) cross‐present antigen (Ag) to initiate T‐cell immunity against most infections and tumors. Natural killer (NK) cells are innate cytolytic lymphocytes that have emerged as key ...modulators of multiple DC functions. Here, we show that human NK cells promote cross‐presentation of tumor cell‐derived Ag by DC leading to Ag‐specific CD8+ T‐cell activation. Surprisingly, cytotoxic function of NK cells was not required. Instead, we highlight a critical and nonredundant role for IFN‐γ and TNF‐α production by NK cells to enhance cross‐presentation by DC using two different Ag models. Importantly, we observed that NK cells promote cell‐associated Ag cross‐presentation selectively by monocytes‐derived DC (Mo‐DC) and CD34‐derived CD11bnegCD141high DC subsets but not by myeloid CD11b+ DC. Moreover, we demonstrate that triggering NK cell activation by monoclonal antibodies (mAbs)‐coated tumor cells leads to efficient DC cross‐presentation, supporting the concept that NK cells can contribute to therapeutic mAbs efficiency by inducing downstream adaptive immunity. Taken together, our findings point toward a novel role of human NK cells bridging innate and adaptive immunity through selective induction of cell‐associated Ag cross‐presentation by CD141high DC, a process that could be exploited to better harness Ag‐specific cellular immunity in immunotherapy.
What's new?
Dendritic cells (DCs) can activate an immune response by ‘presenting’ specific antigens on their surface. In this study, the authors found that when tumor cells are coated with therapeutic antibodies (mAbs), natural killer (NK) cells are activated to trigger the presentation of tumor antigens by special subsets of DCs. They also found that IFN‐γ and TNF‐α are crucial to this process. These results support the concept that NK cells can contribute to the efficacy of therapeutic mAbs by inducing anti‐tumor adaptive immunity.
Statins are widely used hypocholesterolemic drugs that inhibit 3‐hydroxy‐3‐methyl‐glutaryl‐coenzyme A reductase, a rate‐limiting enzyme of the mevalonate pathway whose biosynthetic endproduct is ...cholesterol. As a result of this activity, statins may perturb the composition of cell membranes, resulting in lipid raft disruption. Furthermore, by inhibiting protein prenylation, a process also dependent on mevalonate, statins block membrane targeting and activity of small GTPases. Antigen uptake, processing and presentation involve the interplay of Rab and Rho family GTPases. Furthermore, lipid rafts have been implicated both in antigen internalization by the BCR and in MHC class II clustering at the immunological synapse. Here we have addressed the effects of simvastatin on antigen processing and presentation by human B cells and dendritic cells. The results show that simvastatin potently suppresses tetanus toxoid processing and presentation to CD4+ T cells by HLA‐DR by inhibiting protein antigen uptake through both receptor‐mediated endocytosis and macropinocytosis. This effect can be largely accounted for by defective prenylation of Rho and Rab GTPases in the absence of any measurable perturbation of lipid rafts. In addition, simvastatin was found to preferentially affect the invariant chain‐dependent MHC class II pathway, thereby identifying this route of antigen processing and presentation as a selective target of statins.
The human papillomavirus (HPV) family comprises more than 170 different types that preferentially infect the mucosa of the genitals, upper-respiratory tract, or the skin. The 'high-risk HPV type', a ...sub-group of mucosal HPVs, is the cause of approximately 5% of all human cancers, which corresponds to one-third of all virus-induced tumours. Within the high-risk group, HPV16 is the most oncogenic type, being responsible for approximatively 50% of all worldwide cervical cancers. Many studies suggest that, in addition to the high-risk mucosal HPV types, certain cutaneous HPVs also have a role in the development of non-melanoma skin cancer (NMSC). Functional studies on the HPV early gene products showed that E6 and E7 play a key role in carcinogenesis. These two proteins use multiple mechanisms to evade host immune surveillance, allowing viral persistence, and to deregulate cell cycle and apoptosis control, thus facilitating the accumulation of DNA damage and ultimately cellular transformation. The demonstration that high-risk HPV types are the etiological agents of cervical cancer allowed the implementation in the clinical routine of novel screening strategies for cervical lesions, as well as the development of a very efficient prophylactic vaccine. Because of these remarkable achievements, there is no doubt that in the coming decades we will witness a dramatic reduction of cervical cancer incidence worldwide.
Innate immunity is the first line of host defense against infections. Many oncogenic viruses can deregulate several immune-related pathways to guarantee the persistence of the infection. Here, we ...show that the cutaneous human papillomavirus 38 (HPV38) E6 and E7 oncoproteins suppress the expression of the double-stranded DNA sensor Toll-like receptor 9 (TLR9) in human foreskin keratinocytes (HFK), a key mediator of the antiviral innate immune host response. In particular, HPV38 E7 induces TLR9 mRNA downregulation by promoting accumulation of ΔNp73α, an antagonist of p53 and p73. Inhibition of ΔNp73α expression by antisense oligonucleotide in HPV38 E6/E7 HFK strongly rescues mRNA levels of TLR9, highlighting a key role of ΔNp73α in this event. Chromatin immunoprecipitation experiments showed that ΔNp73α is part of a negative transcriptional regulatory complex with IκB kinase beta (IKKβ) that binds to a NF-κB responsive element within the TLR9 promoter. In addition, the Polycomb protein enhancer of zeste homolog 2 (EZH2), responsible for gene expression silencing, is also recruited into the complex, leading to histone 3 trimethylation at lysine 27 (H3K27me3) in the same region of the TLR9 promoter. Ectopic expression of TLR9 in HPV38 E6/E7 cells resulted in an accumulation of the cell cycle inhibitors p21(WAF1) and p27(Kip1), decreased CDK2-associated kinase activity, and inhibition of cellular proliferation. In summary, our data show that HPV38, similarly to other viruses with well-known oncogenic activity, can downregulate TLR9 expression. In addition, they highlight a new role for TLR9 in cell cycle regulation.
The mucosal high-risk HPV types have been clearly associated with human carcinogenesis. Emerging lines of evidence suggest the involvement of certain cutaneous HPV types in development of skin squamous cell carcinoma, although this association is still under debate. Oncogenic viruses have evolved different strategies to hijack the host immune system in order to guarantee the persistence of the infection. Their capability to evade the immune system is as important as their ability to promote cellular transformation. Therefore, understanding the viral mechanisms involved in viral persistence is a valid tool to evaluate their potential role in human carcinogenesis. Here, we show that E6 and E7 oncoproteins from the cutaneous HPV38 downregulate the expression of the double-stranded DNA sensor TLR9 of innate immunity. We also present evidence that the HPV38-mediated downregulation of TLR9 expression, in addition to its potential impact on the innate immune response, is linked to cell cycle deregulation.
Statins are cholesterol-lowering drugs extensively used for primary and secondary prevention of cardiovascular events related to hypercholesterolemia. Because of their capacity to inhibit HMG-CoA ...reductase, statins also block the production of isoprenoids required for post-translational modification of proteins such as Ras superfamily GTPases, which are master regulators in signaling pathways triggered by surface receptors. As such, statins have pleiotropic effects on many cell types. In the immune system, statins harbor strong anti-inflammatory properties, which result from their capacity to interfere with the activation of proinflammatory cells, including macrophages and endothelial cells. More recently, T-lymphocytes have been identified as cellular targets of statins. Here we shall review recent findings, which document an inhibitory activity of statins on T-cell activation, proliferation, differentiation to Th1 cells and migration across the blood-brain barrier. The therapeutic perspectives of these findings, based on animal models and ongoing clinical trials, will also be discussed.
Cross-presentation of cell-associated Ags by dendritic cells (DC) plays an important role in immunity. DC in lymphoid tissues are short lived, being continuously replaced by precursors that ...proliferate and differentiate locally. Paradoxically, although TLR ligands promote immune responses and stimulate DC replenishment, they impair the cross-priming capacity of terminally differentiated splenic CD8 alpha + DC, the major subset involved in cross-priming. In this study, we have investigated the cross-presentation capacity of newly generated murine DC and especially immediate precursors of CD8 alpha + DC. We show that these DC do not cross-present Ag from dead cells unless stimulated by TLR ligands before Ag capture. TLR ligand CpG induced the expression of costimulatory molecules required for CD8 T cell activation but also regulated the intracellular mechanisms of cross-presentation such as Ag degradation rates without regulating Ag uptake. GM-CSF, an inflammatory cytokine associated with infections, also promoted cross-presentation acquisition by pre-CD8 alpha + DC and synergized with TLR9 ligand. The concept that TLR ligands as well as inflammatory cytokines promote the acquisition of cross-presenting properties by pre-CD8 alpha + DC has important implications during immune responses and when considering the use of these cells for vaccination.
Anthrax is an infection caused by pathogenic strains of Bacillus anthracis, which secretes a three-component toxic complex consisting of protective antigen (PA), edema factor (EF), and lethal factor ...(LF). PA forms binary complexes with either LF or EF and mediates their entry into host cells. Although the initial phases of bacterial growth occur in the lymph node, the host fails to mount an effective immune response. Here, we show that LT and ET are potent suppressors of human T cell activation and proliferation triggered through the antigen receptor. Both LT and ET inhibit the mitogen-activated protein and stress kinase pathways, and both toxins inhibit activation of NFAT and AP-1, two transcription factors essential for cytokine gene expression. These data identify a novel strategy of immune evasion by B. anthracis, based on both effector subunits of the toxic complex, and targeted to a key cellular component of adaptive immunity.
ABSTRACT
Statins are widely used hypocholesterolemic drugs that inhibit 3‐hydroxy‐3‐methylglutaryl‐coenzyme A (HMG‐CoA) reductase, a rate‐limiting enzyme of the mevalonate pathway whose biosynthetic ...end product is cholesterol. In addition to lowering circulating cholesterol, statins perturb the composition of cell membranes, resulting in disruption of lipid rafts, which function as signaling platforms in immunoreceptor signaling. Furthermore, by inhibiting protein prenylation, a process also dependent on mevalonate, statins block membrane targeting and hence activity of small GTPases, which control multiple pathways triggered by these receptors. T‐cell activation is crucially dependent on Ras, Rho and Rab GTPases. Furthermore TCR signaling is orchestrated at lipid rafts, identifying T‐cells as potential cellular targets of statins. Here we report that simvastatin suppresses T‐cell activation and proliferation as the result of its capacity to inhibit HMG‐CoA reductase. T‐cell treatment with simvastatin does not affect intracellular cholesterol levels or raft integrity nor, accordingly, the initial tyrosine phosphorylation‐dependent cascade. Conversely, inhibition of protein prenylation by simvastatin results in a dramatic impairment in the pathways regulated by small GTPases, including the Ras/MAP kinase pathway, the Rac/stress kinase pathway, and the Rab‐dependent pathway of receptor endocytosis. The results identify Ras superfamily GTPases as strategic molecular targets in T‐cell immunosuppression by statins.
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