Category: Immune System

Categories : Immune SystemTags :

How Vitamin A Enters into Gut Immune Cells

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Source: Pixabay

Researchers have reported in Science how vitamin A enters immune cells in the intestines – findings that could offer insight to treat digestive diseases and perhaps help improve the efficacy of certain vaccines.

“Now that we know more about this important aspect of immune function, we may eventually be able to manipulate how vitamin A is delivered to the immune system for disease treatment or prevention,” said Lora Hooper, PhD, Chair of Immunology at UT Southwestern, Howard Hughes Medical Institute Investigator.

Vitamin A is a fat-soluble nutrient which is converted to retinol and then to retinoic acid before it is used. It is important for every tissue in the body, said Dr. Hooper, Professor of Immunology, Microbiology, and in the Center for the Genetics of Host Defense at UT Southwestern. It is particularly crucial for the adaptive immune system, a subset of the broader immune system that reacts to specific pathogens based on immunological memory, the type formed by exposure to disease or vaccines.

Although researchers knew that some intestinal immune cells called myeloid cells can convert retinol to retinoic acid, how they acquire retinol to perform this task was a mystery, said Dr. Hooper, whose lab investigates how resident intestinal bacteria influence the biology of humans and other mammalian hosts.

Lead author Ye-Ji Bang, PhD, a postdoctoral fellow in the Hooper Lab, and colleagues focused on serum amyloid A proteins, a family of retinol-binding proteins that some organs produce during infections. They used biochemical techniques to determine which cell surface proteins they attached to, and identified LDL receptor-related protein 1 (LRP1).

Drs. Bang, Hooper, Herz, and colleagues showed that LRP1 was present on intestinal myeloid cells, where it seemed to be transferring retinol inside. When the researchers deleted the gene for this receptor in mice, preventing their myeloid cells from taking up the vitamin A derivative, the adaptive immune system in their gut virtually disappeared, said Dr Hooper. T and B cells and the molecule immunoglobulin A, critical components of adaptive immunity, were significantly reduced. Researchers then compared the response to Salmonella infection between mice with LRP1 and those without. Those without the receptor quickly succumbed to the infection.

The findings suggest that LRP1 is what conveys retinol into myeloid cells. If a way could be developed to inhibit this process, explained Dr Hooper, it could calm down the immune response in inflammatory diseases that affect the intestines, such as inflammatory bowel disease and Crohn’s disease. Alternatively, boosting LRP1 activity could boost immune activity, making oral vaccines more effective.

Source: UT Southwestern Medical Center

Categories : COVID Immune SystemTags :

Almost ‘Superhuman’ Immune Response Found in Certain People

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Photo by Klaus Nielsen from Pexels

A series of studies in recent months has found that, thanks to the mRNA vaccine and previous infection, some people mount an extraordinarily powerful immune response against SARS-CoV-2 which some scientists have referred to as ‘superhuman’.

Called ‘hybrid immunity’, their bodies produce very high levels of antibodies, with great flexibility: likely capable of fighting off the SARS-CoV-2 variants currently circulating but also likely effective against future variants.

“Overall, hybrid immunity to SARS-CoV-2 appears to be impressively potent,” Crotty wrote in commentary in Science published in June.

“One could reasonably predict that these people will be quite well protected against most  and perhaps all of — the SARS-CoV-2 variants that we are likely to see in the foreseeable future,” says Paul Bieniasz, a virologist at Rockefeller University who helped lead several of the studies.

Bieniasz and his colleagues found antibodies in these individuals capable of strongly neutralising the six variants of concern tested, including Delta and Beta, as well as several other viruses related to SARS-CoV-2, including SARS-CoV-1.

“This is being a bit more speculative, but I would also suspect that they would have some degree of protection against the SARS-like viruses that have yet to infect humans,” Bieniasz said.

People who have had a ‘hybrid’ exposure to the virus, were infected with it in 2020 and then immunised with mRNA vaccines this year. “Those people have amazing responses to the vaccine,” said virologist Theodora Hatziioannou at Rockefeller University, who also helped lead several of the studies. “I think they are in the best position to fight the virus. The antibodies in these people’s blood can even neutralize SARS-CoV-1, the first coronavirus, which emerged 20 years ago. That virus is very, very different from SARS-CoV-2.”

These antibodies were so effective they were even able to deactivate a virus purposefully engineered to be highly resistant to neutralisation, containing 20 mutations that are known to prevent SARS-CoV-2 antibodies from binding to it. Antibodies from those who were only vaccinated or who only had prior coronavirus infections were ineffecgtive against this engineered virus..

This shows how powerful the mRNA vaccine can be in those infected with SARS-CoV-2, she said. “There’s a lot of research now focused on finding a pan-coronavirus vaccine that would protect against all future variants. Our findings tell you that we already have it.

The catch is getting COVID. “After natural infections, the antibodies seem to evolve and become not only more potent but also broader. They become more resistant to mutations within the [virus].”

Hatziioannou and colleagues don’t know if this applies to all those mRNA-vaccinated and previously COVID-infected. “We’ve only studied the phenomena with a few patients because it’s extremely laborious and difficult research to do,” she said.
“With every single one of the patients we studied, we saw the same thing.” The study reports data on 14 patients.

Several other studies lend credence to her hypothesis and reinforce the idea that exposure to both a coronavirus and an mRNA vaccine triggers an exceptionally powerful immune response. In one study in NEJM, scientists analysed antibodies generated by people who had been infected with SARS-CoV-1 back in 2002 or 2003 and who then received an mRNA vaccine this year.

Remarkably, these people also produced high levels of antibodies that could neutralise a whole range of variants and SARS-like viruses. Many questions remain, such as the effect of a third booster shot, or being infected again.

“I’m pretty certain that a third shot will help a person’s antibodies evolve even further, and perhaps they will acquire some breadth [or flexibility], but whether they will ever manage to get the breadth that you see following natural infection, that’s unclear.”

Immunologist John Wherry, at the University of Pennsylvania, is a bit more hopeful. “In our research, we already see some of this antibody evolution happening in people who are just vaccinated,” he said, “although it probably happens faster in people who have been infected.”

In a recent study, Wherry and colleagues showed that, over time, uninfected people with only two doses of the vaccine begin to produce more flexible antibodies, so a third dose would give even more of an evolutionary boost to the antibodies, Wherry said. So a person will be better equipped to fight off whatever variant the virus puts out there next.

“Based on all these findings, it looks like the immune system is eventually going to have the edge over this virus,” said Bieniasz, of Rockefeller University. “And if we’re lucky, SARS-CoV-2 will eventually fall into that category of viruses that gives us only a mild cold.”

Source: NPR

Categories : Immune SystemTags :

Degree of Platelet Drop, Not Count, Important in Sepsis Mortality

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Photo by National Cancer Institute on Unsplash

Mortality risk in sepsis is linked to the degree of platelet reduction, rather than absolute platelet count, according to new Japanese research.

Sepsis, a potentially life-threatening condition, arises from tissue and organ damage from an overactive infection response. Sepsis is commonly characterised by abnormally low platelet counts, which is believed to be associated with its high mortality rate.

Recently, Nagoya University researchers and colleagues have shown that a high degree of platelet reduction, rather than an abnormally low platelet count, raises mortality risks in sepsis. The findings, recently presented in the journal Scientific Reports, could lead to the development of precise and preventive treatments for sepsis-associated coagulopathy.

It is known that during sepsis, disseminated intravascular coagulation (DIC) forms tiny blood clots throughout the bloodstream, depleting platelets. Based on this, the international criterion for the diagnosis of sepsis-associated DIC uses platelet count and trials have been done using this criterion. However, very few trials have led to the development of effective treatments for sepsis-associated DIC.

There is however a different theory, that degree of platelet depletion (a rapid drop), rather than the absolute platelet count, accounts for much mortality risk in sepsis-associated DIC. But since there is little evidence for this theory, it has not been considered an international criterion for the disease prognosis.

With this in mind, researchers conducted a study to examine the significance of the degree of platelet reduction on sepsis mortality rate, using data from 200 859 sepsis patients staying in intensive care units of 208 US hospitals.

Corresponding author Dr Daisuke Kasugai of the Nagoya University Hospital, said: “To our knowledge, it was the largest study to evaluate the prognostic impact of both the degree of platelet depletion and absolute platelet counts in patients with sepsis.”

The degree of platelet reductions was found to be associated with the mortality risk associated with sepsis, regardless of absolute platelet count, indicating higher mortality risk with a fast decrease in platelet count. Dr Kasugai said:  “Surprisingly, we also found that if the platelet count decreases by 11% or more, the risks of bleeding, as well as thrombosis development (a serious condition caused by the formation of blood clots in blood vessels or the heart), increases.”

The researchers therefore concluded that, compared to the absolute platelet count, the degree of platelet reduction could be a more plausible criterion for assessing the mortality risk of the sepsis-associated DIC. They hope that this study will lead to effective treatments for sepsis-associated DIC.

Source: Nagoya University

Categories : COVID Immune SystemTags :

Metabolic Changes in Plasma, Immune Cells Linked to COVID Severity

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Analysing plasma from patients infected with SARS-CoV-2, researchers have uncovered underlying metabolic changes that regulate how immune cells react to COVID, these are associated with disease severity and could be used to predict patient survival. The findings were published in the journal Nature Biotechnology.

“We know that there are a range of immune responses to COVID, and the biological processes underlying those responses are not well understood,” said co-first author Jihoon Lee, a graduate student at Fred Hutchinson Cancer Research Center. “We analyzed thousands of biological markers linked to metabolic pathways that underlie the immune system and found some clues as to what immune-metabolic changes may be pivotal in severe disease. Our hope is that these observations of immune function will help others piece together the body’s response to COVID. The deeper understanding gained here may eventually lead to better therapies that can more precisely target the most problematic immune or metabolic changes.”

The researchers performed two draws on each of nearly 200 patients during the first week after being diagnosed with SARS-CoV-2 infection, and analysed their plasma and single immune cells. The analysis included 1387 genes involved in metabolic pathways and 1050 plasma metabolites.

Increased COVID severity was found to be associated with metabolite alterations, which suggests increased immune-related activity. In addition, each major immune cell type was found to have a distinct metabolic signature.

“We have found metabolic reprogramming that is highly specific to individual immune cell classes (eg “killer” CD8+ T cells, “helper” CD4+ T cells, antibody-secreting B cells, etc.) and even cell subtypes, and the complex metabolic reprogramming of the immune system is associated with the plasma global metabolome and are predictive of disease severity and even patient death,” said co-first and co-corresponding author Dr. Yapeng Su, a research scientist at Institute for Systems Biology. “Such deep and clinically relevant insights on sophisticated metabolic reprogramming within our heterogeneous immune systems are otherwise impossible to gain without advanced single-cell multi-omic analysis.”

“This work provides significant insights for developing more effective treatments against COVID. It also represents a major technological hurdle,” said Dr. Jim Heath, president and professor of ISB and co-corresponding author on the paper. “Many of the data sets that are collected from these patients tend to measure very different aspects of the disease, and are analysed in isolation. Of course, one would like these different views to contribute to an overall picture of the patient. The approach described here allows for the sum of the different data sets to be much greater than the parts, and provides for a much richer interpretation of the disease.”

Source: Max Planck Institute

Categories : Ageing Immune SystemTags :

Traitorous Immune Cells Explain Why the Elderly Feel the Cold

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Photo by Adam Birkett on Unsplash

In a new study, Yale researchers found that the immune cells within fat that are designed to burn calories to protect us from cold temperatures start to turn against us as we age, making the elderly more vulnerable to the cold.

The study, published in Cell Metabolism, found that the fat tissue of older mice loses the immune cell group 2 innate lymphoid cells (ILC2) which restore body heat in cold temperatures. However, trying to stimulate production of new ILC2 cells in aging mice actually makes them more prone to cold-induced death, showing how difficult it is to solve aging-related problems.

“What is good for you when you are young, can become detrimental to you as you age,” said Vishwa Deep Dixit, the Waldemar Von Zedtwitz Professor of Comparative Medicine and of Immunobiology and co-corresponding author of the study.

Prof Dixit and former colleague Emily Goldberg, now an assistant professor at UCSF, were curious about why there are immune cells in fat tissue, as they are usually concentrated in pathogen-exposed areas like nasal passages, lungs, and skin. When they sequenced genes from cells of old and young mice they found that older animals lacked ILC2 cells, a deficit which limited their ability to burn fat in cold conditions.

When they introduced a molecule that boosts the production of ILC2 in aging mice, the immune system cells were restored but the mice were surprisingly even less tolerant of cold temperatures.

“The simple assumption is that if we restore something that is lost, then we are also going to restore life back to normal,” Dixit said. “But that is not what happened. Instead of expanding healthy cells of youth, the growth factor ended up multiplying the bad ILC2 cells that remained in fat of old mice.”

However, when ILC2 cells were taken from younger mice and transplanted into older mice, the older animals’ cold tolerance was restored.

“Immune cells play a role beyond just pathogen defense and help maintain normal metabolic functions of life,” Dixit said. “With age, the immune system has already changed and we need to be careful how we manipulate it to restore the health of the elderly.”

Source: SciTech Daily

Categories : Immune SystemTags :

Tissue Memory T Cells Could be the Future of Vaccination

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Source: Pixabay

Researchers have described how tissue-resident memory T (TRM) cells  behave in different tissues around the body, in a step towards novel, long-lasting vaccines.

Applications include second generation COVID vaccines, that would target lung tissue directly.

TRM cells are an immune cell that are exclusively found in tissues, not in circulation or the blood, and have been found to be critical for immune protection against viral infection and are also able to control melanoma growth in the skin.

In this study, led by University of Melbourne Professor Laura Mackay and published in Nature Immunology, examined the behaviour of TRM cells in a number of different body tissues.

By comparing barrier organs that are exposed to the environment, like the skin, to solid organs such as the liver, the team found that the location in which TRMs are raised significantly impacts the way they contribute to immunity, demonstrating that “one size does not fit all” when it comes to these cells.

Postdoctoral researcher Dr Susan Christo said that discovering the distinct molecular signatures and behaviours of TRM cells in specific tissues will help the development of effective T cell-based vaccines and immunotherapies.

“For example, if you want effective T-cell mediated immunity against a respiratory virus like SARS-CoV-2 or influenza, you want to induce TRM cells in the lung. That way, the memory of the infection exists at the site of potential pathogen encounter,” Dr Christo said.

“We found that TRM cells act like chameleons when they enter into a new tissue — they rapidly adapt to the molecules and proteins around them and can take on a new ‘image’ or phenotype.

“The tissue surroundings also control how these cells behave — TRM cells in the skin are suppressed by a particular protein called TGF-b which acts like a handbrake to stop these cells from unnecessary activation that may cause autoimmunity, such as psoriasis, but still allows them to fight against dangers like melanoma.

“One key advantage of skin TRM cells is that they can last a really long time and will be ready to attack when the body is in true danger.

The team found the TRMs inside the liver do not have this TGF-b brake, and so have a greater ability to form a bigger pool of cells.

“You could think of them as generating a large army of soldiers that fight the infection. However liver TRMs have a shorter half-life and might not be around to fight future battles,” Dr Christo explained.

“To give the example of malaria, if you want to target immune cells in the liver, you need to work out what needs to be done to make those cells live longer.

“This is also the case for short-lived TRM cells in the lung, which has significant implications on the durability of vaccines against the flu and COVID. Therefore, our study provided the first evidence of what our immune cells need to last the distance and protect us for a long time.”

Source: Medical Xpress

Categories : Immune SystemTags :

Lipid Shield Protects Both Immune and Cancer Cells

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Colourised scanning electron microscope image of a natural killer cell. Credit: National Institutes of Health

A newly discovered lipid ‘shield’ that prevents natural killer cells from being destroyed by their own deadly biological weapons also allows some cancer cells to evade an immune system attack, a study at Columbia University has found.

The findings, which may lead to new treatments for aggressive cancers, were published in the journal PLoS Biology.

Natural killer cells are efficient assassins that can eliminate up to six infected or cancer cells each day. The deadly immune cells grab onto their target and blast it with toxic proteins and enzymes that punch holes in the cell’s membrane. But these substances are also capable of destroying the natural killer cell’s membrane during the attack.

But how do natural killer cells survive releasing this blast of deadly substances? “I’ve been working on natural killer cells since the early 1990s, and every time I gave a talk about these cells, someone always asked that question,” said study leader and immunology expert Jordan Orange, MD, PhD, a professor at Columbia University Vagelos College of Physicians and Surgeons. “And nobody really knew until now.”

Avoiding self-destruction

Yu Li, a graduate student working with Prof Orange to understand how natural killer cells work and co-author of the study, thought the answer might lie in the double layer of lipids that makes up the outer membranes of all cells. Compared with other cells, Li noticed, the membranes of natural killer cells looked more orderly and more densely packed with lipids when viewed under a microscope.

“There were a lot of hypotheses about why natural killer cells don’t kill themselves during their attack on other cells, but they all proposed there might be a magic, unknown protein protecting these cells,” Li says. But Li had doubts. “Based on biophysical considerations, I didn’t think a protein would be strong enough to protect the cells. When I looked at the cells, I thought of lipids.”

To test out his idea, he exposed the membranes to a compound that weakens the structure of the lipid layer. With less dense and less orderly membranes, the natural killer cells were unprotected from their own toxic blast—and perished along with their targets.

Shields up

To survive their own toxic blast natural killer cells reinforce their membranes immediately beforehand, Li found. The small granules holding the deadly substances move to the outer edge of the natural killer cell. As the granule unleashes its cargo into the space between the killer and target cells, its own unusually dense lipid membrane merges with and reinforces the natural killer cell membrane.

“In essence, Li found that the membrane turns into a blast shield,” Prof Orange says. “And the protection comes from the way the membrane’s lipids are arranged. When the lipids are arranged in a more orderly fashion, more lipids can be packed into the membrane. The toxic substances simply can’t find a way into the membrane,” Orange says.

Cancer cells steal the idea

Besides natural killer cells, some cancer cells have adopted this defence against natural killer cells’ attacks, Li and Prof Orange found. They may also use this as a defence from cytotoxic T cells, another immune cell that uses lipids for self-protection.

Li found that cells from an aggressive breast cancer known to be impervious to natural killer cells fortify their membranes during the attack. The reinforcement was vital for the cancer cells, Li discovered, because when he added a membrane compound that disrupts lipid packing, the cancer cells were rendered vulnerable.

“We don’t know yet if this is a general mechanism by which cancer cells resist natural killer cells,” Li said. “If it is generalisable, we can start to think of therapies that disrupt the tumor cell membrane and make it more susceptible to attack by the immune system.” 

Source: Medical Xpress

Categories : Cardiovascular Disease Immune SystemTags :

ACE Inhibitors Reduce Immune Defence against Bacteria

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Neutrophil interacting with two pink-colored, rod shaped, multidrug-resistant (MDR), Klebsiella pneumoniae
Neutrophil interacting with two pink-colored, rod shaped, multidrug-resistant (MDR), Klebsiella pneumoniae. Photo by CDC on Unsplash

Scientists have found evidence suggesting that giving patients ACE inhibitors reduces the ability of their immune system to resist bacterial infections.  the group describes testing of multiple ACE inhibitors in mice and human cells.

ACE inhibitors are typically given to patients with hypertension, and some instances to people with heart failure, kidney disease or diabetes. The drugs relaxes the walls of arteries, veins and capillaries, reducing blood pressure. Some prior studies had shown that the drugs also help the immune system by boosting neutrophils, which are produced to fight bacteria. In this new study, published in the journal Science Translational Medicine, the researchers have found the opposite to be true.

In order to see the effects of ACE inhibitors on the immune system, researchers at Cedars-Sinai Medical Center administered different brands of ACE inhibitor such as Zestril and Altace, to mice and then tested their ability to resist bacterial infections. Compared to untreated mice, those with the ACE inhibitors had greater difficulty in recovering from bacterial infections such as staph.

Seven human patients who were taking an ACE inhibitor volunteered blood samples to measure their immune response. The researchers found that the neutrophils were unable to produce the molecules needed to fight off bacteria. They were also found to be in vitro ineffective against bacteria.

The researchers also tested another drug used to treat hypertension, an angiotensin II receptor drug, Cozaar. These drugs work by preventing arterial walls from constricting, which reduces blood pressure. They found no evidence of a negative impact on immunity. They did not test beta-blockers, which work by preventing adrenergic receptors from being stimulated, reducing cardiac action.

The researchers concluded that administering ACE inhibitors to patients puts them at an increased risk of bacterial infections, noting that doctors may want to try alternative drugs to treat their patients.

Source: MedicalXpress

Journal information: Duo-Yao Cao et al, An ACE inhibitor reduces bactericidal activity of human neutrophils in vitro and impairs mouse neutrophil activity in vivo, Science Translational Medicine (2021). DOI: 10.1126/scitranslmed.abj2138

Categories : COVID Immune SystemTags :

T Cells Unnecessary for COVID Recovery

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Infected cell covered with SARS-CoV-2 viruses (yellow). Source: NIAID

New research with monkeys reveals that primates do not need T cells for the recovery of from acute COVID infections.

T cell depletion was also found not to induce severe disease, and T cells do not explain the natural resistance of rhesus macaques to severe COVID. Furthermore, it was found that strongly T cell-depleted macaques still develop potent memory responses to a second infection.

The findings, published in mBio, an open-access journal of the American Society for Microbiology, have implications for the development of second-generation vaccines and therapeutics.

Lead study author Kim Hasenkrug, PhD, senior investigator in the Laboratory of Persistent Viral Diseases, National Institutes of Health, explained: “We started this study early in the pandemic, trying to figure out how to make a good model to study the disease in humans using animals. The monkeys turned out to be more resistant to the disease than we expected, so we wanted to try to figure out why that was and try to gain some insights into the disease in humans as well. We now know that the antibody response is the most critical response for protection by vaccination, not the T cell response.”

In the new study, the researchers used classic reagents known to deplete CD4+ and CD8+ T cells in rhesus macaques. CD8+ T cells attack infected cells and kill them, and CD4+ T cells are helper T cells that set off the immune response by recognising pathogens and secreting cytokines, which signal other immune cells to act, including CD8+ T cells and antibody-producing B cells.

One week after depleting the macaques of CD4+ T cells, CD8+ T cells, or both at the same time, the researchers infected the animals with SARS-CoV-2. “We depleted, we infected them and then we continued the depletions during the first week of infection to make sure the animals were well depleted. Then we studied their blood to see how they were responding in terms of their T cells and B cells,” said Hasenkrug. Nasal swabs and bronchoalveolar lavages were performed over six weeks to measure virus in the nose, mouth and lungs, along with rectal swabs to check for virus shedding in the gut. After six weeks, the monkeys were re-challenged with SARS-CoV-2 and virus and blood samples collected, which let the researchers evaluate immune memory responses. “If there is a memory response, you get a much quicker immune response and control of the virus. That is how vaccinations work. Once your body has seen a viral pathogen, the next time it sees it, you can get a much faster and stronger immune response,” said Dr Hasenkrug.

Unexpected response

Even with T cell depletion, the monkeys were still able to mount a good memory response against the virus. “We found we got really good memory responses regardless of whether we depleted T cells or not. Basically, we found very strong virus neutralising antibodies, and they are the most important antibodies in controlling the infection. That was unexpected by most immunologists, virologists and vaccinologists,” said Dr Hasenkrug.

“The other thing that happens during a memory response is that antibodies mature, becoming stronger and more potent at binding the viral pathogen. We saw indications of this through what’s called ‘class switching’,” said Dr Hasenkrug.

‘Class switching’ was also not expected in these monkeys with depleted T cells. “We don’t have a firm explanation as to why that happened, but we think it involves some sort of compensatory response, which you can see in our study. For example, when we depleted CD8+ T cells, we saw stronger CD4+ T cell or B cells responses in some animals. When the animals are missing something, they will try to make up for it by making more of something else.”

Dr Hasenkrug doesn’t know why the T cells turned out to be not very important, but this may be a good thing, since people who fail to mount sufficient T cell responses still have opportunities to recover.

“This implies that the innate immune response is critical for initial control of the virus, rather than the adaptive immune responses we studied,” said Hasenkrug.

Source: American Society for Microbiology

Journal information: Hasenkrug, K.J., et al. (2021) Recovery from Acute SARS-CoV-2 Infection and Development of Anamnestic Immune Responses in T Cell-Depleted Rhesus Macaques. mBio. doi.org/10.1128/mBio.01503-21.

Categories : Cancer Immune SystemTags :

Unleashing the Immune System to Attack Cancers

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Shown here is a pseudo-colored scanning electron micrograph of an oral squamous cancer cell (white) being attacked by two cytotoxic T cells (red), part of a natural immune response. Photo by National Cancer Institute on Unsplash

A potential treatment has been identified, that could boost the immune system’s ability to find and destroy cancer cells, by impeding certain cells which regulate the immune system, which in turn can unleash other immune cells to attack tumours in cancer patients.

“A patient’s immune system is more than able to detect and remove cancer cells and immunotherapy has recently emerged as a novel therapy for many different types of cancers,” explained study leader Nullin Divecha, Professor of Cell Signalling at the University of Southampton. “However, cancer cells can generate a microenvironment within the tumour that stops the immune system from working thereby limiting the general use and success of immunotherapy,” he continued.

One of a number of types of T cells, Teffector cells (Teffs) carry out the task of detection and removal of cancer cells . How well Teff cells work in detecting and removing cancer cells is partly governed by other T cells called T-regulatory cells, or Tregs for short. Tregs physically interact with the Teff cells, producing molecules which dampen the functioning of the Teff cells.

Prof Divecha added, “Tregs carry out an important function in the human body because without them, the immune system can run out of control and attack normal cells of the body. However, in cancer patients we need to give the Teff cells more freedom to carry out their job.”

Molecules released by tumour cells exacerbate the problem by attracting and gathering Tregs, reducing the activity and function of Teff cells even further. Though there are mechanisms to inhibit Treg cells, since Treg and Teff cells are very similar, Teff cells are also generally inhibited.

In this new study, published in PNAS, scientists from the University of Southampton and the National Institute of Molecular Genetics in Milan showed that inhibition of a family of enzymes in cells called PIP4K could be the answer to how to restrict Tregs without affecting Teffs.

The research team isolated Tregs from healthy donors and used genetic technology to suppress the production of the PIP4K proteins. They saw that loss of PIP4Ks from Treg cells stopped their growth and response to immune signals, in turn stopping them from impeding Teff cell growth and function.

Importantly, the loss of the same enzymes in Teff cells did not limit their activity.

“This was surprising because PIP4Ks are in both types of T cells in similar concentrations but our study shows that they seem to have a more important function for Tregs than Teffectors,” said Dr. Alessandro Poli who carried out the experimental research.

Scientists must next develop molecules in order to inhibition of PIP4K as a potential therapy for patients. “Towards this end we show that treatment with a drug like inhibitor of PIP4K could enable the immune system to function more strongly and be better equipped to destroy tumour cells.”

Source: EurekAlert!