High Extracellular K Skews T-Cell Differentiation Towards Tumour Promoting Th2 and T Subsets.

Potassium ions (K) released from dying necrotic tumour cells accumulate in the tumour microenvironment (TME) and increase the local K concentration to 50 mM (high-[K]). Here, we demonstrate that high-[K] decreases expression of the T-cell receptor subunits CD3ε and CD3ζ and co-stimulatory receptor CD28 and thereby dysregulates intracellular signal transduction cascades. High-[K] also alters the metabolic profiles of T-cells, limiting the metabolism of glucose and glutamine, consistent with functional exhaustion.

Spatially-resolved transcriptomics reveal macrophage heterogeneity and prognostic significance in diffuse large B-cell lymphoma.

Macrophages are abundant immune cells in the microenvironment of diffuse large B-cell lymphoma (DLBCL). Macrophage estimation by immunohistochemistry shows varying prognostic significance across studies in DLBCL, and does not provide a comprehensive analysis of macrophage subtypes. Here, using digital spatial profiling with whole transcriptome analysis of CD68+ cells, we characterize macrophages in distinct spatial niches of reactive lymphoid tissues (RLTs) and DLBCL.

Effects of Different Anticoagulation Doses on Moderate-to-Severe COVID-19 Pneumonia With Hypoxemia.

Background COVID-19 is a prothrombotic disease that can cause thromboembolism and microthrombi, which could lead to multiorgan failure and death. Since COVID-19 is a relatively new disease, there are guidelines for anticoagulation dosing for COVID-19 patients without consensus on the dosing. We studied the effects of different doses of anticoagulation in hospitalized patients with COVID-19 pneumonia and hypoxemia on any differences in need for high-flow oxygen, mechanical ventilation, and mortality.

Structure of the voltage-gated potassium channel K1.3: Insights into the inactivated conformation and binding to therapeutic leads.

The voltage-gated potassium channel K1.3 is an important therapeutic target for the treatment of autoimmune and neuroinflammatory diseases. The recent structures of K1.

Interaction of the Inhibitory Peptides ShK and HmK with the Voltage-Gated Potassium Channel K1.3: Role of Conformational Dynamics.

Peptide toxins that adopt the ShK fold can inhibit the voltage-gated potassium channel K1.3 with IC values in the pM range and are therefore potential leads for drugs targeting autoimmune and neuroinflammatory diseases. Nuclear magnetic resonance (NMR) relaxation measurements and pressure-dependent NMR have shown that, despite being cross-linked by disulfide bonds, ShK itself is flexible in solution.

Obstacles for T-lymphocytes in the tumour microenvironment: Therapeutic challenges, advances and opportunities beyond immune checkpoint.

The tumour microenvironment (TME) imposes a major obstacle to infiltrating T-lymphocytes and suppresses their function. Several immune checkpoint proteins that interfere with ligand/receptor interactions and impede T-cell anti-tumour responses have been identified. Immunotherapies that block immune checkpoints have revolutionized the treatment paradigm for many patients with advanced-stage tumours.

Mechanisms Underlying C-type Inactivation in Kv Channels: Lessons From Structures of Human Kv1.3 and Fly Shaker-IR Channels.

Voltage-gated potassium (Kv) channels modulate the function of electrically-excitable and non-excitable cells by using several types of "gates" to regulate ion flow through the channels. An important gating mechanism, C-type inactivation, limits ion flow by transitioning Kv channels into a non-conducting inactivated state. Here, we highlight two recent papers, one on the human Kv1.

Imaging Kv1.3 Expressing Memory T Cells as a Marker of Immunotherapy Response.

Immune checkpoint inhibitors have shown great promise, emerging as a new pillar of treatment for cancer; however, only a relatively small proportion of recipients show a durable response to treatment. Strategies that reliably differentiate durably-responding tumours from non-responsive tumours are a critical unmet need. Persistent and durable immunological responses are associated with the generation of memory T cells.

Rearrangement of a unique Kv1.3 selectivity filter conformation upon binding of a drug.

We report two structures of the human voltage-gated potassium channel (Kv) Kv1.3 in immune cells alone (apo-Kv1.3) and bound to an immunomodulatory drug called dalazatide (dalazatide-Kv1.

Kv1.3 Channel Up-Regulation in Peripheral Blood T Lymphocytes of Patients With Multiple Sclerosis.

Voltage-gated Kv1.3 potassium channels are key regulators of T lymphocyte activation, proliferation and cytokine production, by providing the necessary membrane hyper-polarization for calcium influx following immune stimulation. It is noteworthy that an accumulating body of and evidence links these channels to multiple sclerosis pathophysiology.

CD4 T Cells Mediate the Development of Liver Fibrosis in High Fat Diet-Induced NAFLD in Humanized Mice.

Non-alcoholic fatty liver disease (NAFLD) has been on a global rise. While animal models have rendered valuable insights to the pathogenesis of NAFLD, discrepancy with patient data still exists. Since non-alcoholic steatohepatitis (NASH) involves chronic inflammation, and CD4 T cell infiltration of the liver is characteristic of NASH patients, we established and characterized a humanized mouse model to identify human-specific immune response(s) associated with NAFLD progression.

Modulation of Lymphocyte Potassium Channel K1.3 by Membrane-Penetrating, Joint-Targeting Immunomodulatory Plant Defensin.

We describe a cysteine-rich, membrane-penetrating, joint-targeting, and remarkably stable peptide, EgK5, that modulates voltage-gated K1.3 potassium channels in T lymphocytes by a distinctive mechanism. EgK5 enters plasma membranes and binds to K1.

Contributions of natural products to ion channel pharmacology.

Covering: Up to 2020Ion channels are a vast super-family of membrane proteins that play critical physiological roles in excitable and non-excitable cells. Their biomedical importance makes them valuable and attractive drug targets for neurological, cardiovascular, gastrointestinal and metabolic diseases, and for cancer therapy and immune modulation. Current therapeutics target only a minor subset of ion channels, leaving a large unexploited space within the ion channel field.

Extracellular K Dampens T Cell Functions: Implications for Immune Suppression in the Tumor Microenvironment.

Dying tumor cells release intracellular potassium (K), raising extracellular K ([K]) in the tumor microenvironment (TME) to 40-50 mM (high-[K]). Here, we investigated the effect of high-[K] on T cell functions. Functional impacts of high-[K] on human T cells were determined by cellular, molecular, and imaging assays.

Antibodies and venom peptides: new modalities for ion channels.

Ion channels play fundamental roles in both excitable and non-excitable tissues and therefore constitute attractive drug targets for myriad neurological, cardiovascular and metabolic diseases as well as for cancer and immunomodulation. However, achieving selectivity for specific ion channel subtypes with small-molecule drugs has been challenging, and there currently is a growing trend to target ion channels with biologics. One approach is to improve the pharmacokinetics of existing or novel venom-derived peptides.

The combined activation of K3.1 and inhibition of K11.1/hERG1 currents contribute to overcome Cisplatin resistance in colorectal cancer cells.

Background: Platinum-based drugs such as Cisplatin are commonly employed for cancer treatment. Despite an initial therapeutic response, Cisplatin treatment often results in the development of chemoresistance. To identify novel approaches to overcome Cisplatin resistance, we tested Cisplatin in combination with K channel modulators on colorectal cancer (CRC) cells.

A Non-invasive Way to Isolate and Phenotype Cells from the Conjunctiva.

Traditionally, ocular surface cytology is studied with techniques such as spatula technology and brush technology. The problem with these techniques is that they may induce traumatic lesions on the surface of the eye, which can progress to scarring, eyelid deformity, limbal stem cell deficiency and in some cases, cause great discomfort to the subject. To avoid these clinical problems, impression cytology (IC) was developed to diagnose dry eye disease and later neoplasia, atopic disease, vernal keratoconjunctivitis and keratoconjunctivitis sicca.

Venom-derived peptide inhibitors of voltage-gated potassium channels.

Voltage-gated potassium channels play a key role in human physiology and pathology. Reflecting their importance, numerous channelopathies have been characterised that arise from mutations in these channels or from autoimmune attack on the channels. Voltage-gated potassium channels are also the target of a broad range of peptide toxins from venomous organisms, including sea anemones, scorpions, spiders, snakes and cone snails; many of these peptides bind to the channels with high potency and selectivity.

A Chronic Autoimmune Dry Eye Rat Model with Increase in Effector Memory T Cells in Eyeball Tissue.

Dry eye disease is a very common condition that causes morbidity and healthcare burden and decreases the quality of life. There is a need for a suitable dry eye animal model to test novel therapeutics to treat autoimmune dry eye conditions. This protocol describes a chronic autoimmune dry eye rat model.

Peptide blockers of K1.3 channels in T cells as therapeutics for autoimmune disease.

The voltage-gated K1.3 channel in T lymphocytes is a validated therapeutic target for diverse autoimmune diseases. Here we review the discovery of K1.

Tissue resident memory T cells in the human conjunctiva and immune signatures in human dry eye disease.

Non-recirculating resident memory (T) and recirculating T cells mount vigorous immune responses to both self and foreign antigens in barrier tissues like the skin, lung and gastrointestinal tract. Using impression cytology followed by flow cytometry we identified two T subsets and four recirculating T-subsets in the healthy human ocular surface. In dry eye disease, principal component analysis (PCA) revealed two clusters of patients with distinct T-cell signatures.

International Union of Basic and Clinical Pharmacology. C. Nomenclature and Properties of Calcium-Activated and Sodium-Activated Potassium Channels.

A subset of potassium channels is regulated primarily by changes in the cytoplasmic concentration of ions, including calcium, sodium, chloride, and protons. The eight members of this subfamily were originally all designated as calcium-activated channels. More recent studies have clarified the gating mechanisms for these channels and have documented that not all members are sensitive to calcium.

Kv1.3 channel-blocking immunomodulatory peptides from parasitic worms: implications for autoimmune diseases.

The voltage-gated potassium (Kv) 1.3 channel is widely regarded as a therapeutic target for immunomodulation in autoimmune diseases. ShK-186, a selective inhibitor of Kv1.