A closer look at rebel T cells

Video Credit: La Jolla Institute

Scientists at La Jolla Institute for Immunology (LJI) are investigating a talented type of T cell.

Most T cells only work in the person who made them. Your T cells fight threats by responding to molecular fragments that belong to a pathogen—but only when these molecules are bound with markers that come from your own tissues. Your influenza-fighting T cells can’t help your neighbor, and vice versa.

“However, we all have T cells that do not obey these rules,” says LJI Professor and President Emeritus Mitchell Kronenberg, Ph.D. “One of these cell types is mucosal-associated invariant T (MAIT) cells.”

Now Kronenberg and his LJI colleagues have uncovered another MAIT cell superpower: MAIT cells can recognize the same markers whether they come from humans or mice. Kronenberg calls this finding “astounding.” “Humans diverged from mice in evolution 60 million years ago,” he says.

This new research, published in Science Immunology, sheds light on the genes and nutrients that give MAIT cells their fighting power. The findings are an important step toward one day harnessing these cells to treat infectious diseases and improve cancer immunotherapies.

Researchers identify previously unknown step in cholesterol absorption in the gut

Illustration Credit: Scientific Frontline

UCLA researchers have described a previously unknown step in the complex process by which dietary cholesterol is processed in the intestines before being released into the bloodstream – potentially revealing a new pathway to target in cholesterol treatment.

Although an existing drug and statins impact part of the process, an experimental drug being studied in UCLA research labs appears to specifically target the newfound pathway, possibly adding a new approach to the cholesterol management toolbox.

“Our results show that certain proteins in the Aster family play a critical role in moving cholesterol through the absorption and uptake process,” said Dr. Peter Tontonoz, a UCLA professor and researcher in Pathology and Laboratory Medicine and Biological Chemistry, senior author of an article in Science. “The Aster pathway appears to be a potentially attractive target for limiting intestinal cholesterol absorption and reducing levels of plasma cholesterol.”

Cholesterol from food is absorbed by cells that line the inner surface of the intestines – enterocytes – where it is processed into droplets that eventually reach the bloodstream. But this journey involves a multistep process.

Antibodies to Cow’s Milk Linked to Increased Risk of Cardiovascular Death

Corinne Keet, MD, PhD, pediatric allergy and immunology professor in the UNC Department of Pediatrics
Photo Credit: Courtesy of University of North Carolina School of Medicine

Sensitivity to common food allergens such as cow’s milk and peanuts could be an important and previously unappreciated cause of heart disease, new research suggests – and the increased risk for cardiovascular death includes people without obvious food allergies.

In a paper published in The Journal of Allergy and Clinical Immunology that describes analyses led by Corinne Keet, MD, PhD, pediatric allergy and immunology professor in the UNC Department of Pediatrics of two longitudinal studies, the authors show that the people who produced IgE antibodies to cow’s milk and other foods were at significantly increased risk of cardiovascular mortality. This was true even when traditional risk factors for heart disease, such as smoking, high blood pressure, and diabetes were accounted for. The strongest link was for cow’s milk, but IgE to other allergens such as peanut and shrimp were also significant among those who eat the foods.

This troubling finding represents the first time that IgE antibodies to common foods have been linked to increased risk of cardiovascular mortality, the researchers report. The findings do not conclusively prove that food antibodies are causing the increased risk, but the work builds on previous studies connecting allergic inflammation and heart disease.

Extracellular vesicles captured using sustainable wood cellulose-based nanofiber sheets may identify and improve cancer treatment

Researchers developed a technique using cellulose nanofiber (CNF) sheets to capture extracellular vesicles (EVs). Extracting and analyzing EVs using this technology has the potential to revolutionize early cancer diagnosis and open the door to personalized medicine.
Image Credit: Takao Yasui

A research team in Japan, led by Nagoya University’s Akira Yokoi, has developed an innovative technique using cellulose nanofiber (CNF) sheets derived from wood cellulose to capture extracellular vesicles (EVs) from fluid samples and even organs during surgery. EVs are small structures from cancerous cells that play a crucial role in cell-to-cell communication. Extracting and analyzing EVs using this new technology has the potential to revolutionize early cancer diagnosis and open the door to personalized medicine. The researchers published their findings in Nature Communications. 

Cancer is notorious for its poor prognosis and in many cases goes undetected until its advanced stages, leaving patients with limited treatment options. Detecting the cancer early using EVs and analyzing them provides vital information on disease status and its progression. This should assist physicians in monitoring and adjusting personalized cancer treatment plans. However, researchers have been limited in previous attempts to use EVs due to the lack of an effective isolation strategy. 

New antifungal molecule kills fungi without toxicity in human cells, mice

The mechanism for a critical but highly toxic antifungal is revealed in high resolution. Self-assembled Amphotericin B sponges (depicted in light blue) rapidly extract sterols (depicted in orange and white) from cells. This atomic level understanding yielded a novel kidney-sparing antifungal agent. 
Illustration Credit: Jose Vazquez

A new antifungal molecule, devised by tweaking the structure of prominent antifungal drug Amphotericin B, has the potential to harness the drug’s power against fungal infections while doing away with its toxicity, researchers at the University of Illinois Urbana-Champaign and collaborators at the University of Wisconsin-Madison report in the journal Nature.

Amphotericin B, a naturally occurring small molecule produced by bacteria, is a drug used as a last resort to treat fungal infections. While AmB excels at killing fungi, it is reserved as a last line of defense because it also is toxic to the human patient – particularly the kidneys. 

Scientists engineer potent immune cells for ‘off-the-shelf’ cancer immunotherapy

Illustration Credit: Scientific Frontline

UCLA scientists have developed a new method to engineer more powerful immune cells that can potentially be used for “off-the-shelf” cell therapy to treat challenging cancers.

“Off-the-shelf” cell therapy, also known as allogenic therapy, uses immune cells derived from healthy donors instead of patients. The approach can bring cell therapies, like chimeric antigen receptor (CAR) T cell therapy, to more patients in a timelier manner, which is one of the major barriers in getting these life-saving treatments to patients.

“Time is often of the essence when it comes to treating people with advanced cancers,” said Lili Yang, associate professor of microbiology, immunology and molecular genetics and member of the UCLA Health Jonsson Comprehensive Cancer Center. “Currently, these types of therapies need to be tailored to the individual patient. We have to extract white blood cells from a patient, genetically engineer the cells and then re-infuse them back into the patient. This process can take weeks to months and can cost hundreds of thousands of dollars to treat each patient.”

New strategy may halt tumors' aggressive response to glucose deprivation

The figure shows the expression of a differentiation marker in the tumors of mice treated with the glucose inhibitor, the epigenetic inhibitor, or both. Top left image is the placebo, top right is the glucose inhibitor, bottom left is the epigenetic inhibitor and bottom right is the glucose inhibitor and epigenetic inhibitor. The brown signal indicates the presence of the differentiation marker. The treatment with the glucose inhibitor (top right) reduces the brown signal, whereas the addition of the epigenetic inhibitor rescues the expression of the differentiation marker.
Image Credit: Dr. Claudio Scafoglio.

One of the hallmarks of cancer cell development is its dependence on sugar, especially glucose, to grow and divide. Scientists have long been studying how to restrict or block this process that promotes tumor growth, called glycolysis, from happening as a possible effective strategy against cancer.

Previously, researchers from the UCLA Health Jonsson Comprehensive Cancer Center identified a specific protein sodium glucose transporter 2, or SGLT2, as a mechanism that lung cancer cells can utilize to obtain glucose. Drugs that inhibit SGLT2 are already FDA approved for other conditions and the UCLA team found these drugs could also delay the development of lung cancer and improved survival when tested in mice, suggesting these drugs could be repurposed for lung cancer treatment.

However, while inhibiting glycolysis can slow down the growth of tumors, the researchers found it can also make cancer cells more aggressive, making the cancer harder to treat. This led the team to look at other mechanisms of resistance in the tumors that still grow while being treated with SGLT2 inhibition that may link glucose restriction to increases aggression.

People with prior illness more likely to report longer symptoms after COVID-19 infection

Photo Credit: Kelly Sikkema

The study from King’s College London, which is published on the pre-print server MedRxiv and has not been peer-reviewed, shows that while two thirds of individuals with post-COVID illness were healthy before infection, individuals with long illness duration were significantly more likely to have similar symptoms 1-2 months before developing COVID-19.

Most people with COVID-19 recover completely within a few days or weeks. However, some report ongoing symptoms including fatigue, ‘brain fog’, sneezing, a runny nose and headache long after infection. For some individuals, this may manifest as long COVID.

In this study, researchers first analyzed data from over 23,000 ZOE Symptom Study app users, who reported their health (whether healthy or unhealthy) at least once weekly, both before and after they had COVID-19. They found that individuals who had symptoms before they caught SARS-CoV-2 infection were significantly more likely to have a longer illness duration.

The researchers then assessed 1350 adults who reported long-term symptoms after COVID-19 (at least eight weeks, with nearly a thousand having symptoms for more than 12 weeks), matched with 1350 individuals whose symptoms had resolved within four weeks.

World’s first smart breathing tube for mechanically ventilated patients set for human trials

Professor Steve Morgan
Photo Credit: Courtesy of University of Nottingham

The University of Nottingham has secured £1.1 million in funding from the Medical Research Council to undertake human trials for the world’s first optical fiber sensor-equipped endotracheal tube (iTraXS).

Seriously ill or anaesthetized patients are unable to breathe naturally, so clinicians often use endotracheal tubes (ETTs), which are placed in the trachea (windpipe) to maintain an open airway and allow the patient to breathe through a mechanical ventilator. To do this, the tube is placed into the airway and a cuff (balloon) is inflated at the trachea to create a gas seal that allows air to be delivered to the lungs effectively. However, incorrect cuff inflation pressure can cause two main problems.

If pressure is too low, it can risk fluid getting past the cuff and causing ventilator-associate pneumonia (VAP). VAP increases the likelihood of death, affecting up to 20% of people in intensive care, and costs the NHS between £10,000 and £20,000 per patient. Conversely, if pressure is too high it can cause a pressure injury in the trachea, ranging from moderate to severe sore throats through to permanent scarring and narrowing of the windpipe.

Success of Wolbachia-infected mosquitoes in fighting dengue may be underestimated

Alex Perkins, associate professor of biological science
Photo Credit: Courtesy of University of Notre Dame

The fight against dengue fever has a new weapon: a mosquito infected with the bacteria Wolbachia, which prevents the spread of the virus. These mosquitoes have now been deployed in several trials demonstrating their potential in preventing disease transmission.

Now, researchers at the University of Notre Dame have conducted an analysis of the World Mosquito Program’s randomized control trial of Wolbachia-infected mosquitoes in Indonesia, looking at how excluding transmission dynamics impacted the original interpretation of the trial’s results.

“Randomized controlled trials are the gold standard for evaluating the efficacy of any medical or public health intervention. That is very difficult for vector interventions against dengue because incidence of the disease can be somewhat unpredictable and sporadic, requiring very large-scale trials,” said Alex Perkins, associate professor of biological sciences at Notre Dame and senior author on the study.

Improving the efficacy of cancer immunotherapy with modified CAR-T cells

Water color art illustrates the publication by Velasco et al. The authors systematically engineered novel Chimeric Antigen Receptors (CARs), each containing one of the signaling chains of the natural T cell receptor: epsilon, gamma, delta and zeta (from left to right, from top to bottom) to create innovative CAR T cells. The work demonstrated that each signaling chain imprints the functioning of the CAR T cells (represented by the different colors) impacting thus their anti-tumor activity.
Illustration Credit: Sara Wossning Minguet

CAR-T cell therapy is a last hope for many patients with blood, bone marrow or lymph gland cancer when other treatments such as chemotherapy are unsuccessful. A limiting factor of this otherwise very effective and safe therapy is that the cells used in the process quickly reach a state of exhaustion. Researchers at the University of Freiburg have now been able to prevent this exhaustion and thus significantly improve the effect of the therapy in a preclinical animal model. The new results have been published in the journal Nature Immunology.

Using the body’s own defenses against cancer

CAR-T cells are one of the personalized cancer therapies and have been used in specialized centers in Europe since 2018. In this complex treatment, immune cells, or more precisely T cells, are taken from the blood of cancer patients, genetically engineered in the laboratory with a chimeric antigen receptor (CAR) and then re-administered. The receptor helps the T cells to identify and kill cancer cells. As a result, the therapy utilizes the body’s own cells to permanently eradicate the cancer.

Higher risk of 17 cancers after high BMI in late teens

Aron Onerup, Institute of Clinical Sciences, and Maria Åberg, Institue of Medicine, Sahlgrenska Academy at the University of Gothenburg.
Photo Credit: Anna Onerup, Johan Wingborg

Men who are overweight or obese at age 18 have a higher risk of 17 different cancers later in life. This has been shown in a study at the University of Gothenburg. The research also describes how the youth obesity epidemic is expected to affect the cancer situation over the next 30 years.

In August, a study on higher cancer risk in men who had lower aerobic fitness recorded at the time of compulsory conscription for military service at the age of 18 was presented. The results were independent of any overweight or obesity at conscription.

In two new studies published in the journals Obesity and Cancer Medicine, the same research team is now focusing on body mass index (BMI), while the results are independent of the participants' aerobic fitness level. And it turns out that higher BMI at age 18 can be linked to even more cancers later in life than poor fitness at the same age.

High BMI at conscription was associated with a higher risk of 17 cancers: lung, head and neck, brain, thyroid, esophageal, stomach, pancreatic, liver, colon, rectal, kidney, and bladder cancer, as well as malignant melanoma, leukemia, myeloma, and lymphoma (both Hodgkin's and non-Hodgkin's).

New study findings call into question the superiority of stem cell therapy for treating knee pain

Image Credit: rawpixel

Characterized by extensive damage to joints and debilitating pain, osteoarthritis (OA) impacts millions of people worldwide and has long posed a substantial clinical and economic burden.

In spite of advances in diagnosis, medications, and short-term pain management solutions, the elusive goal of a disease-modifying OA drug has remained out of reach. In recent years though, the use of stem cell therapy has gained traction as a promising alternative to surgery and for improving patients’ quality of life.  

Through a grant from the Marcus Foundation, an Emory team of investigators in collaboration with other recruitment sites throughout the nation explored the potential of mesenchymal stem cells as a game-changing treatment option for knee OA, one of the most common causes of chronic knee pain. This type of treatment seeks to harness the ability of a patient’s own cells to repair damaged tissue. However, the availability of robust data from well-designed randomized controlled trials has been limited, particularly in comparison to the gold-standard of treatment for knee OA, corticosteroid injections (CSI).

One Punch Isn’t Enough to Overcome a Common Cancer Mutation

Acute myeloid leukemia as seen under a microscope.
Image Credit: Animalculist
(CC BY-SA 4.0)

Cancer cells are often a mess of mutations. About 20 to 25 percent of cancers involve mutations in a complex of molecules called SWI/SNF. Yet drugs designed to block SWI/SNF activity haven’t always worked as expected.

Researchers at Harvard Medical School have now figured out why.

As reported Nov. 2 in Cell, the team found that when drugs block SWI/SNF, a second molecule steps up to compensate.

Blocking this second molecule alongside SWI/SNF suppressed cancer cell growth in lab dishes, suggesting that a two-drug approach could make treatments more effective in people.

“I am excited about this work because it shows an alternative path forward for treating cancers in which the SWI/SNF complex is mutated,” said senior author Karen Adelman, the Edward S. Harkness Professor of Biological Chemistry and Molecular Pharmacology in the Blavatnik Institute at HMS, whose lab conducted the work.

“What’s interesting and meaningful about this study is it shows that a one-two punch, a double-agent therapy, could be really useful for keeping these cancer cells at bay,” she said.

Atherosclerosis: RNA fragment creates prospect for new therapies

Image Credit: © Weber Lab, IPEK

Atherosclerosis is considered a frequent cause of cardiovascular diseases and strokes. Despite medical progress, case numbers are constantly rising. Targeted new therapeutic approaches are therefore more important than ever. An international team led by Professor Christian Weber, Director of the Institute for Cardiovascular Prevention (IPEK) at the University Hospital of Munich, and Professor Donato Santovito, leader of the Translational Vascular Therapy research group at IPEK, has now identified a specific microRNA molecule as a promising starting point for the investigation of new therapies.

Some time ago, the researchers had already demonstrated that the transmembrane protein CXCR4 plays a significant role in the development of atherosclerosis. The protein transmits signals to the cell interior. If CXCR4 is specifically silenced in arterial endothelial cells or in smooth muscle cells, it results in more severe atherosclerotic lesions. At the same time, there is increased leukocyte ingress into the cell, which leads to inflammatory processes. With regard to leukocytes, however, the presence of CXCR4 can also promote the development of inflammatory processes. “It made sense, therefore, to only boost the expression of CXCR4 on the cells of the vascular wall in order to counteract the atherosclerosis,” says Santovito. “The challenge, however, is not to influence any biological processes, as the protein occurs in all cells and exercises various important functions.”

New antibodies neutralize resistant bacteria

Cryo-electron microscopic reconstruction of the binding of a human anti-PcrV Fab antibody (yellow) to a PcrV pentamer (blue) of the type III secretion system (T3SS) of Pseudomonas aeruginosa. The antibody binding leads to an inhibition of the T3SS, which is an important virulence factor of P. aeruginosa.
Image Credits: CSSB/Biao Yuan

A research team has discovered antibodies that could lead to a new approach to treating acute and chronic infections with the bacterium Pseudomonas aeruginosa. Due to its numerous resistance mechanisms, P. aeruginosa is associated with high morbidity and mortality and can cause complicated infections and dangerous cases of sepsis in severely ill patients. The team of scientists from the University of Cologne, University Hospital Cologne, the Helmholtz Centre for Infection Research in Braunschweig and University Hospital Hamburg-Eppendorf isolated the antibodies from immune cells of chronically ill patients and described their binding mechanisms. The study ‘Discovery of highly neutralizing human antibodies targeting Pseudomonas aeruginosa’ was published in the renowned scientific journal Cell.

Antibiotic-resistant bacteria are a crucial health concern worldwide not only to infected people, but also to our healthcare systems in general. Infections with the bacterium P. aeruginosa in particular are a threat due to numerous resistance mechanisms, often leading to complicated infections of the lungs and dangerous sepsis, especially in severely ill patients. In addition, the pathogen can permanently colonize organs such as the lungs, where it promotes progressive tissue damage. Often, so-called last-resort antibiotics must be used to treat infected patients, as the standard treatments no longer work. New therapeutic approaches are therefore urgently needed to ensure effective treatment for infections with multi-resistant pathogens such as P. aeruginosa in the future.

Preventing the Exhaustion of T Cells

Healthy (red) and exhausted (green) T cells in the spleen of chronically infected mouse.
Image Credit: Ana Maria Mansilla / Institut für Systemimmunologie, Universität Würzburg

In the immune system's fight against cancer and infections, the T cells often lose their power. The team of Würzburg immunologist Martin Vaeth has found a possible explanation for this phenomenon.

In the immune system, chronic infections and the defense against tumors often lead to the phenomenon of T cell exhaustion: In this process, the T lymphocytes gradually lose their function, which impairs their responses against cancer and infections. The molecular mechanisms that control this loss of function have not been fully unraveled.

It is now certain that the exhaustion process is significantly influenced by the “powerhouses of the cells”, the mitochondria.

When mitochondrial respiration fails, a cascade of reactions is triggered, culminating in the genetic and metabolic reprogramming of T cells – a process that drives their functional exhaustion. But this "burnout" of the T cells can be counteracted: pharmacological or genetic optimization of cellular metabolism increases the longevity and functionality of T cells. This can be achieved, for example, by overexpressing a mitochondrial phosphate transporter that drives the production of the energy-providing molecule adenosine-triphosphate.

Higher risk of cancer following 'all clear' after suspected cancer referral

Photo Credit: National Cancer Institute

Patients who were referred to urgent suspected cancer pathways, but were found not to have cancer at that time, have a higher risk of subsequent cancer in the 1-5 years following the ‘all clear’ than those who haven’t been through the referral pathways.

The study, published today in Lancet Oncology, is the first to examine the risk of cancer in patients in England who entered the urgent suspected cancer pathway but were found not to have cancer at that time. These patients were found to have a higher-than-expected risk of subsequent cancer in the 1-5 years after the initial ‘all clear’.

In England, the urgent suspected cancer referral pathway is the most common route to diagnosis. Of the 3 million patients who are referred for urgent cancer assessments in England each year, 7% are found to have cancer. This leaves a large group of patients who go through these pathways but do not have cancer at the time – a group that is currently understudied and who may be in need of support.

Risk of serious infection even in low-active IBD

Karl Mårild, Institute of Clinical Sciences, Sahlgrenska Academy at the University of Gothenburg.
 Photo Credit: Västra Götalandsregionen

Inflammatory bowel disease (IBD) is an independent risk factor for serious infection, even at very low levels of gastrointestinal inflammation. This has been shown by a study at the University of Gothenburg.

IBD is an umbrella term for chronic inflammatory bowel diseases, with a population prevalence of around 0.5%. The main types of IBD are ulcerative colitis and Crohn’s disease. Unlike irritable bowel syndrome (IBS), IBD results in visible damage to the intestinal mucous membrane.

IBD is characterized by intermittent symptoms. Periods of high disease activity are sometimes followed by longer periods of low or no activity. However, the extent to which IBD patients with low disease activity are also at increased risk of serious infections, including sepsis, has been unclear.

The current study, published in the journal Clinical Gastroenterology and Hepatology, included data on 55,626 individuals diagnosed with IBD. ‘Serious infections’ referred to infections requiring hospitalization.

Fossil fuels responsible for heart arrhythmias in mammals

Photo Credit: Pixabay

One of the most common byproducts of the burning of fossil fuels, phenanthrene, causes heart arrhythmias in mice, proving for the first time it is toxic to mammals, new research has discovered.

The study, led by The University of Manchester in collaboration with the University of Bristol and Moscow State University, and funded by the British Heart Foundation, is published today in the journal Environmental Health Perspectives.

Thanks to earlier work by one of the lead authors Professor Holly Shiels from Manchester in conjunction with scientists at the University of Bristol, Moscow State University, National Oceanic and Atmospheric Association (NOAA) and Stanford University, phenanthrene's toxicity to the hearts of fish and crustaceans (crayfish) has been well established.

But now the team has discovered the change also occurs in healthy mouse hearts when directly exposed to phenanthrene, mimicking what happens when we breathe in pollution.

Professor Holly Shiels said: "We've known that phenanthrene is causally linked to cardiotoxicity in fish for many years - scientists recognized this following the disastrous impact of the Exxon Valdez oil disaster in Alaska in 1989.