B7 family checkpoint regulators in immune regulation and disease
Geisel School of Medicine at Dartmouth, Department of Microbiology and Immunology, Norris Cotton Cancer Centre, 1 Medical Center Drive, Lebanon, New Hampshire 03756, USA. Trends in Immunology
(Impact Factor: 10.4).
08/2013; 34(11). DOI: 10.1016/j.it.2013.07.003
Fine-tuning the immune response and maintaining tolerance to self-antigens involves a complex network of co-stimulatory and co-inhibitory molecules. The recent FDA approval of ipilimumab, a monoclonal antibody blocking cytotoxic T lymphocyte antigen (CTLA)-4, demonstrates the impact of checkpoint regulators in disease. This is reinforced by ongoing clinical trials targeting not only CTLA-4, but also the programmed death (PD)-1 and B7-H4 pathways in various disease states. Recently, two new B7 family inhibitory ligands, V-domain Ig suppressor of T cell activation (VISTA) and B7-H6 were identified. Here, we review recent understanding of B7 family members and their concerted regulation of the immune response to either self or foreign pathogens. We also discuss clinical developments in targeting these pathways in different disease settings, and introduce VISTA as a putative therapeutic target.
Available from: Djo Hasan
- "d. Important immune resistance mechanisms involve, amongst others, immunosuppressive myeloid derived suppressor cells (MDSCs) and immune‐inhibitory pathways, termed immune checkpoints (see below, under the escape phase chapter), which normally (in inflammatory processes other than tumour environment) mediate immune tolerance and mitigate collateral tissue damage [Kanterman J, et al., Semin Cancer Biol 2012; Pardoll DM, Nat Rev Cancer 2012; Ceeraz S, et al., Trends Immunol 2013] Comparison of the cellular environment of tumours in equilibrium versus those that escape: higher proportions of CTLs, NKs, γδ T‐cells and lower proportions of NKT‐cells, Foxp3+ Treg cells, and MDSCs are associated with the equilibrium phase. This means that tolerance and rejection of the tumour cells (which are regulated by the immune "
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Every normal cell has the capability to eliminate itself when its DNA is damaged. This, amongst others, to prevent the development of cancer cells. But, sometimes the genes that are involved in intrinsic tumour suppression are damaged, the intrinsic tumour suppression mechanism fails and cancer cells may survive. There is evidence that all tumour cells originate from myeloid derived stem cells. Thus, cancer is an immune disease.
Tumour cells have certain properties: the hallmarks of cancer. These are: 1) Unlimited replicative potential and replicative immortality; 2) Resisting cell death; 3) Self-sufficiency in growth signals; 4) Insensitivity to anti-growth signals; 5) Evasion of contact inhibition and the ability to invade and migration (metastasis); 6) The ability to attract and sustain angiogenesis for nutrient supply; 7) The ability to suppress the immune system.
The immune reaction to eliminate cancer cells is called the extrinsic tumour suppression. This type of tumour suppression engages only after the intrinsic tumour suppression has failed. Cancer immunoediting is the process of cancer elimination by the immune system. This process is complex and can be simplified into three phases: 1) The elimination phase (= the immunosurveillance); 2) The equilibrium phase (= the immunoselection); 3) The escape phase (= the immunosubversion). In the latter case, the tumour mass is uncontrollable by the immune system and cancer cells may grow, invade the surroundings and metastasise. The tumour mass consist of tumour stem cells, more or less maturated tumour cells, cancer associated fibroblasts (CAFs), tumour associated macrophages (TAMs), regulatory T-cells (Tregs), myeloid derived suppressor cells (MDSCs or MSCs), etc. This tumour matrix protects the tumour cells from being destroyed by the immune system. In other words: the patient’s own immune system protects the tumour cells within the tumour mass. Apparently, an individual tumour cell is far more vulnerable to the immune system than a tumour mass with its defensive tumour matrix. Chronic inflammation plays a crucial role in the development of the tumour matrix.
The best treatment option is to remove all tumour masses completely by means of radical curative surgery and treatment of the underlying chronic inflammation. Unfortunately, this is not always possible. In these cases, modern cancer therapy consists of: the combination of debulking surgery, treatment of the underlying chronic inflammation, immunotherapy to specifically attack the tumour cells, and immunotherapy to weaken the tumour protection by the tumour matrix.
Available from: Xabier Urra
- "Reduction of infarct volume after transient ischemia was achieved by immune regulation of myelin-reactive inflammatory T cells using recombinant T cell receptor ligands (RTL), i.e., partial MHC class II molecules covalently bound to myelin peptides acting as partial agonists that deviate autoreactive T cells to become non-pathogenic (Subramanian et al., 2009; Dziennis et al., 2011), again supporting a negative effect of antigen-specific responses in the lesion caused by stroke. Co-inhibitory molecules, like PD-1, regulate the induction and maintenance of peripheral tolerance (Ceeraz et al., 2013). Accordingly, PD-1-deficient mice showed higher inflammatory responses, infarct volume and neurological deficits after brain ischemia (Ren et al., 2011b). "
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ABSTRACT: Brain proteins are detected in the cerebrospinal fluid (CSF) and blood of stroke patients and their concentration is related to the extent of brain damage. Antibodies against brain antigens develop after stroke, suggesting a humoral immune response to the brain injury. Furthermore, induced immune tolerance is beneficial in animal models of cerebral ischemia. The presence of circulating T cells sensitized against brain antigens, and antigen presenting cells (APCs) carrying brain antigens in draining lymphoid tissue of stroke patients support the notion that stroke might induce antigen-specific immune responses. After stroke, brain proteins that are normally hidden from the periphery, inflammatory mediators, and danger signals can exit the brain through several efflux routes. They can reach the blood after leaking out of the damaged blood-brain barrier (BBB) or following the drainage of interstitial fluid to the dural venous sinus, or reach the cervical lymph nodes through the nasal lymphatics following CSF drainage along the arachnoid sheaths of nerves across the nasal submucosa. The route and mode of access of brain antigens to lymphoid tissue could influence the type of response. Central and peripheral tolerance prevents autoimmunity, but the actual mechanisms of tolerance to brain antigens released into the periphery in the presence of inflammation, danger signals, and APCs, are not fully characterized. Stroke does not systematically trigger autoimmunity, but under certain circumstances, such as pronounced systemic inflammation or infection, autoreactive T cells could escape the tolerance controls. Further investigation is needed to elucidate whether antigen-specific immune events could underlie neurological complications impairing recovery from stroke.
Available from: Gavin W G Wilkinson
- "The T cell costimulators ICOSLG (inducible T cell costimulator ligand) and PD-L2 were downregulated during infection, as was butyrophilin subfamily 3 member A1 (BTN3A1), recently shown to present phosphoantigens to Vg9Vd2 + T cells (Vavassori et al., 2013). V-domain Ig suppressor of T cell activation (VISTA, C10Orf54), a novel B7 family inhibitory ligand (Ceeraz et al., 2013) was upregulated late in infection (Figure 4B). NK and T cell ligands belong to a few key protein families, including cadherins, C-type lectins, immunoglobulin, TNF receptor , and major histocompatibility-complex-related molecules (Vivier et al., 2008). "
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ABSTRACT: A systematic quantitative analysis of temporal changes in host and viral proteins throughout the course of a productive infection could provide dynamic insights into virus-host interaction. We developed a proteomic technique called “quantitative temporal viromics” (QTV), which employs multiplexed tandem-mass-tag-based mass spectrometry. Human cytomegalovirus (HCMV) is not only an important pathogen but a paradigm of viral immune evasion. QTV detailed how HCMV orchestrates the expression of >8,000 cellular proteins, including 1,200 cell-surface proteins to manipulate signaling pathways and counterintrinsic, innate, and adaptive immune defenses. QTV predicted natural killer and T cell ligands, as well as 29 viral proteins present at the cell surface, potential therapeutic targets. Temporal profiles of >80% of HCMV canonical genes and 14 noncanonical HCMV open reading frames were defined. QTV is a powerful method that can yield important insights into viral infection and is applicable to any virus with a robust in vitro model.
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