Over the last few decades, there has been growing popularity for the ‘hygiene hypothesis’, which suggests that some level of microbial exposure helps protects against developing allergy. Now, an article published in Science Immunology by researchers from Karolinska Institutet challenges this hypothesis by showing that mice with high infectious exposures from birth have the same, if not an even greater ability to develop allergic immune responses than ‘clean’ laboratory mice.
Studies have suggested that certain infections might reduce the production of inflammatory antibodies to allergens and alter the behaviour of T cells involved in allergies. It has also been suggested that ‘good’ intestinal bacteria could shut off inflammation elsewhere in the body.
Robust allergic responses
Researchers have now compared the allergic immune response in ‘dirty’ wildling mice to those of typical clean laboratory mice. They found very little evidence that the antibody response was altered or that the function of T cells changed in a meaningful way. Nor did anti-inflammatory responses evoked by good gut bacteria appear to be capable of switching off the allergic immune response. On the contrary, wildling mice developed robust signs of pathological inflammation and allergic responses when exposed to allergens.
“This was a little unexpected but suggests that it’s not as simple as saying, ‘dirty lifestyles will stop allergies while clean lifestyles may set them off’. There are probably very specific contexts where this is true, but it is perhaps not a general rule,” says Jonathan Coquet, co-author of the study and Associate Professor at Karolinska Institutet.
More like the human immune system
The wildling mice are genetically identical to clean laboratory mice but are housed under ‘semi-natural’ conditions and have rich microbial exposures from birth.
“The immune systems of wildling mice better represent the human immune system and so we hope that they can bring us closer to the truth of how microbes act upon the body,” says Jonathan Coquet.
The findings contribute to the general understanding of how allergies may arise and may also have clinical implications. Using experimental infections to treat patients suffering from inflammatory diseases has also been attempted in recent clinical trials. For example, infecting people with worms or performing faecal transplantations has been proposed as a tool to combat inflammatory diseases. Newborns delivered through C-section, have had maternal faecal transplantation and bacterial supplementation with the aim of promoting good bacteria in the baby’s gut and the child’s future health.
Beneficial effects of exposure not clear as we’d like
“This field of research can provide important insights into how infections and microbes can be used to facilitate health, but it is still in its infancy. Our study is a reminder that general and broad exposures to microbes may not have the clear beneficial effects that we wish them to have,” says Susanne Nylén, co-author of the study and Associate Professor at the Department of Microbiology, Tumor and Cell Biology at Karolinska Institutet.
Adults with atopic dermatitis (AD) have a 34% increased risk of developing new-onset inflammatory bowel disease (IBD) compared to those without the skin condition, according to a new recently published in JAMA Dermatology. The study also shows for children, the risk increase is 44%. Additionally, as the severity of AD increased, the risk of developing IBD rose.
These findings clear up ambiguity from previous research, especially among populations of children and between the different types of IBD: ulcerative colitis and Crohn’s disease. While IBD is located in the gut and AD affects the skin, both diseases are driven by the immune system and are categorised by severe inflammation. Insight offered from this study from the Perelman School of Medicine at the University of Pennsylvania could lead to new treatments for both IBD and AD.
“It is imperative for clinicians to understand atopic dermatitis and the trajectory of our patients with it in order to provide the best standard of care,” said senior author Joel M Gelfand, MD, dermatology professor at Penn. “There are new and better treatments for AD today, and there will likely continue to be more. But providers have to understand how those treatments could impact other autoimmune diseases. For patients with AD and another autoimmune disease, some currently available medications can exacerbate symptoms of their other disease or can help treat two immune diseases at the same time.”
While this is not the first study to explore AD and IBD, its size, with one million adult and child participants with AD drawn from a UK medical database, and its separation between ulcerative colitis and Crohn’s disease advances previous research.
When looking at ulcerative colitis and Crohn’s disease separately, AD was not linked to higher ulcerative colitis in children unless the kids had severe AD. Children with AD, however, had a 54–97% increased relative risk of Crohn’s disease, and among children with severe AD, their risk was roughly five times higher. Results among adults were more straightforward. Adults with AD had a 32% increased relative risk of ulcerative colitis and a 36% increased relative risk of Crohn’s disease. Gelfand notes that the absolute extra risk of developing IBD in individuals with AD is still quite small, but the association is meaningful in better understanding health outcomes in AD. Moreover, since millions of people have AD, this small increase in risk spread among many people is likely important from a public health perspective.
Although Penn researchers did not look at the root cause of IBD linked to AD, they have strong hypotheses about the links.
“AD and IBD can cause changes in the microbiome, chronic inflammation, and the dysfunction in the skin and gut barrier respectively,” said Gelfand, who is also the director of the Center for Clinical Sciences in Dermatology at Penn. “There are also specific cytokines, certain kinds of proteins, that play a role in immune system activity and that seem to be related to AD and IBD. For example, we think dysfunction of types of T cells common to both AD and IBD, could be the culprits. Those need to be explored further to uncover both what’s happening at a microscopic level and what proteins or structures could be targeted to treat one or both conditions.”
As a leading expert on psoriasis, a disease known to be tied to IBD genetically, Gelfand is well aware of how closely skin health can affect other parts of the body. He and his colleagues are also studying AD’s relationship to infections, neurologic and psychiatric disorders, and cardiovascular disease.
“Investigating the relationship between skin diseases and other diseases doesn’t just offer new insight into how these diseases can affect a patient with both, but these studies are especially powerful because they also highlight unique characteristics of each disease and how they behave individually,” Gelfand shared.
Signalling from inflammatory cytokines activates several protein kinases in a chain – at the end of this process MKK6 (yellow) ‘switches on’ p38α (green) by binding it and adding phosphates. The combination of computer simulations, SAXS, and cryo-EM has shown how the two proteins interact and bind to each other to transmit the signal. Credits: Ella Marushchenko, Isabel Romero Calvo/EMBL
Cytokine storms, where inflammatory cascades during an infection that can spiral out of control and lead to severe disease and even death, were recently highlighted during the COVID-19 pandemic. In a new paper published in Science, researchers report their discovery of a cellular ‘switch’ which may lead to new drugs to prevent deadly cytokine storms.
EMBL Grenoble and University of Geneva researchers provide essential insights on a protein called p38α which is an important cellular ‘switch’ triggering the inflammatory response. They have obtained the first structure of p38α being activated by another regulatory protein kinase, MKK6, opening up new directions to develop drugs to stop cytokine storms.
The final switch: a drug target
Matthew Bowler, a researcher at EMBL Grenoble, has been studying kinases for more than a decade. This group of enzymes plays an important role in regulating complex processes in the cell by acting as a ‘switch’ to transmit signals and activate gene expression. They do so by phosphorylation, in which phosphate is added to other molecules to modulate their function.
Bowler’s work particularly focuses on belonging to the Mitogen Activated Protein (MAP) family of kinases, key players involved in the inflammatory response. Inflammation is switched on via a series of kinases, which activate each other in a cascade of reactions, the final kinase in the series being responsible for activating gene transcription required for inflammation. This process releases cytokines, pro-inflammatory signalling molecules, which, in case of overactivation, can lead to cytokine storms.
This kinase chain reaction is well regulated and is similar to a logic circuit: the inflammation response requires specific buttons to be switched on, ultimately activating p38α – the convergence point for all the signals and the last switch of the inflammatory process.
Because the kinase chain reaction can come from different ‘branches’ of the logic circuit, this last switch is a particularly relevant drug target. The inflammatory response is regulated by p38α and is highly activated during a cytokine storm. Inactivating it could prevent inflammation from occurring, instead of trying to treat it while it is already underway.
Protein kinases, including p38α, have therefore been heavily studied. The first protein kinase structure was solved 30 years ago and many more structures have followed, with over 7000 structures now available in the Protein Data Bank.
However, important parts of the puzzles are still missing. “Structural biologists have obtained detailed information on the structure and functions of protein kinases, but mostly in isolation. So we don’t really know how these enzymes are activated along the chain reaction,” explained Bowler.
Without this essential information about how the activation is triggered, drugs have mostly targeted the kinases’ nucleotide-binding site – a common and well-known pocket present in all kinases, where the phosphate transfer occurs. The lack of drug specificity due to a common binding site across kinases means that a drug designed to stop one kinase from signalling could also stop others. This presents a problematic side effect, considering the essential role of kinases as key regulators in cellular processes.
“There are many molecules that have been designed to target p38α, especially its nucleotide-binding site, but none have yet made it past clinical trials due to this lack of specificity,” added Bowler.
Cracking the activation mechanism
Since 2009, Bowler and a former PhD student in his lab, Erika Pellegrini, have therefore been investigating the interactions between p38α and MKK6, the kinase which activates it. But studying the interaction between kinases proves to be extremely complex. “These enzymes are very dynamic molecules; they transmit important signals and need to act quickly. In the case of p38α, it has to go into the nucleus and activate lots of other different proteins,” said Bowler.
They were hampered by the fact that the interactions of the MKK6-p38α complex cannot be determined by macromolecular crystallography, a structural biology technique often employed to investigate proteins but that is particularly challenging to apply in the case of such dynamic proteins.
Recent developments in cryo-electron microscopy (cryo-EM), particularly during the last decade, raised new hopes. In 2016, Bowler and new PhD student and first author of the paper, Pauline Juyoux, decided to switch to this technique – even though the protein complex was at the time considered too small for cryo-EM analysis. They were supported by Pellegrini, who had acquired expertise in this technique.
Using cryo-EM and complementary techniques, such as X-ray crystallography and small-angle X-ray scattering (SAXS), the team managed to obtain the 3D structure of the complex and identify a previously unknown docking site where the two enzymes interact – crucial information for understanding how p38? is activated. “This could be an interesting target for inhibitors that block this specific interaction, and consequently the signal triggering the inflammatory response,” explained Juyoux.
A collaboration with the Gervasio Lab from the University of Geneva, which uses molecular dynamics simulations, provided further insight into how the two kinases interact. “They showed that the model we had generated was compatible with the enzymatic activity and that the phosphorylation site was at the right distance from the active site,” explained Juyoux. “They also classified the different types of conformations of the complex to show how they assemble.”
Crucially, by comparing these simulations with the SAXS data they were able to model how the two proteins interact prior to catalysis. “The beauty of combining the state-of-the-art simulations with SAXS and cryo-EM data through advanced statistical approaches is that we can ‘see’ the dance of the two kinases approaching one another, while knowing that what we see in the computer is fully supported by all the experimental data available,” explained Francesco Gervasio. “The simulations required several months of supercomputing time generously allocated by the Swiss National Supercomputing Centre,” he continued, “But it was well worth it, given the relevance of the final results.”
These results provide an alternative drug target site to explore and also open the door to studying similar processes in two other families of MAP kinases: ERK kinases, which are involved in cancer, and JNK kinases, which are also involved in inflammation, especially in Alzheimer’s disease.
“Kinases are very similar to one another in terms of sequence and structure, but we don’t know how and why they respond or send a specific signal,” said Juyoux, whose current research project as a postdoctoral fellow at Institut de Biologie Structurale in Grenoble focuses on JNK kinases. “Comparing these different families of kinases could help explain the specificity of interactions and lead the way to new therapeutic approaches.”
Researchers have identified stem cells in the human thymus for the first time. These cells represent a potential new target to understand immune diseases and cancer and how to boost the immune system. Their reported their discovery in the journal Developmental Cell.
The thymus is a gland located in the front part of the chest, the place where thymocytes (the cells in the thymus) mature into T cells, specialised immune cells crucial to fighting disease. The thymus has a unique and complex 3D structure, including an epithelium (a lining of cells able to guide T cell maturation) that forms a mesh throughout the whole organ and around the thymocytes.
Owing to its relatively inaccessible location, comparatively recent discovery and the fact that it shrinks with age, the thymus has only been investigated for a short period of time compared to other organs. Until now, scientists believed it didn’t contain ‘true’ epithelial stem cells, but only progenitors arising in foetal development.
However, these findings from researchers at the Francis Crick Institute, show for the first time the presence of self-renewing stem cells, which give rise to the thymic epithelial cells instructing thymocytes to become T cells. This suggests the thymus plays an important, regenerative role beyond childhood, which could be exploited to boost the immune system.
In the course of their experiments, the researchers examined these stem cells based on the expression of specific proteins in the human thymus. They identified stem-cell niches (areas where stem cells are clustered) in two locations in the thymus: underneath the organ capsule, or outer layer, and around blood vessels in the medulla, the central part.
They demonstrated that thymic stem cells contribute to the environment by producing proteins of the extracellular matrix, which functions as their own support system.
By using state-of-the-art techniques to map gene expression in single cells and tissue sections, they found that these stem cells, named Polykeratin cells, express a variety of genes allowing them to give rise to many cell types not previously considered to have a common origin. They can develop into epithelial as well as muscle and neuroendocrine cells, highlighting the importance of the thymus in hormonal regulation.
The researchers isolated Polykeratin stem cells in a dish and were able to show that thymus stem cells can be extensively expanded. They demonstrated that all the complex cells in the thymus epithelium could be produced from a single stem cell, highlighting a remarkable and yet untapped regenerative potential.
Roberta Ragazzini, postdoctoral research associate at the Crick and UCL, and first author, said: “It’s paradoxical that stem cells in the thymus – an organ which reduces in size as we get older – regenerate just as much as those in the skin – an organ which replaces itself every three weeks. The fact that the stem cells give rise to so many different cell types hints at more fundamental functions of the thymus into adulthood.”
It’s understood that the thymus’ activity is tightly regulated in adults, providing enough immune support to fight infections but not overshooting to the degree of attacking the body’s own cells.
However, in certain people, the thymus isn’t working properly, or their immune system has reduced capacity. Today’s findings suggest it could be helpful in these cases to stimulate the stem cells to regrow the thymus and rejuvenate their immune system.
Paola Bonfanti, senior group leader of the Epithelial Stem Cell Biology and Regenerative Medicine Laboratory at the Crick, said: “This research is a pivotal shift in our understanding of why we have a thymus capable of regeneration. There are so many important implications of stimulating the thymus to produce more T cells, like helping the immune system respond to vaccinations in the elderly or improving the immune response to cancer.”
The researchers will next study thymic stem cell properties throughout life and how to manipulate them for potential therapies.
Scanning electron micrograph of a B cell. Credit: NIH
When the immune system is compromised due to various conditions and medicines, patients can experience opportunistic infection. Now, researchers reporting in Cell Reports have uncovered a sex-based variance in the trained immune memory response to infection in mice that might translate to humans.
The researchers, from the University of Missouri School of Medicine, found that female mice were more vulnerable to opportunistic infection from a bacterial pathogen to which they had previously been exposed when progesterone levels were naturally elevated as part of their reproductive cycle.
“Differences in immune response in males and females have been observed before. For instance, males had increased morbidity and severity of COVID-19 from SARS-CoV-2 infections,” said Dr Adam Schrum, associate professor in the Department of Molecular Microbiology and Immunology. “But females are known to suffer other infections worse than males. Our research found that female mice were far more vulnerable to opportunistic bacterial infection than male mice because of a sex-based difference in their trained immunity.”
To understand why the immune systems of female and male mice responded differently to a bacterial pathogen, the researchers examined whether the reproductive cycle affected immune training. They found that elevated progesterone levels correlated with lower trained immune responses. To test this more fully, the researchers gave the female mice progesterone blockers and found that their trained immune response was subsequently enhanced.
“The female mice had significantly restored trained immune response when progesterone was blocked, reaching comparable levels to those of male mice,” said Schrum. “Sex hormone-based modulation of immune function needs more study to be fully understood, but as a first step we can conclude that immune training is influenced by a progesterone-dependent mechanism that results in a sex bias in mice.”
In addition to further study to understand how and why progesterone specifically influences trained immune responses in mice, the researchers pointed out that because mice have shorter estrous cycles than the human menstrual cycle, further research is needed to understand how sex hormones might affect human immune training.
People often say whether they feel like their immune system is ‘down’ – but could there be some truth to this? A recent study showed that when freshly vaccinated people self-assessed the strength of their immune response, their estimates correlated well to their measured antibody levels. They were even more accurate when their immune response was weak. The results were published in the journal Biological Psychology.
At the University of Konstanz, Stephanie psychologist Dimitroff researches the connection between our brain and our immune system. “Listen to your body,” she concludes from her study. “The field of medicine is moving towards greater patient orientation. Our findings support the idea that patients’ self-perceptions provide valuable clues about their state of health. Physicians should listen to them more.”
Communication between the immune and nervous systems
One part of our brain, the insula, receives information from the body and gives us a basic impression of its condition, which until now was assumed to be quite general in nature. Stephanie Dimitroff’s study now suggests that our brain can perceive the body’s condition more specifically than previously thought. Is it possible that our brain can assess the state of our immune system?
“Of course, our brain does not count antibodies. But our immune system is intrinsically connected to the central nervous system,” Dimitroff explains. “The immune system is regulated via this connection. And our brain also receives information from the immune system.”
This communication between the immune system and the central nervous system is key for our sense of well-being or illness. “It is important to know here: When we feel ill, for example, we have a cold, this feeling is caused quite significantly by the immune system’s communication with the central nervous system,” says Dimitroff. “The brain receives signals that something is wrong with the body and causes the feeling of illness as a result.”
The same flow of information between the immune and nervous systems can generally also take place when the body is not ill. This means it could be possible that this communication process gives us an impression of our immune system even when we are healthy. Stephanie Dimitroff’s study investigates whether this is actually the case.
Results of the study
The study looked at people who had received the COVID-19 vaccine. This group of participants was chosen because a particularly large number of people received the vaccine in the summer of 2021, when the study was conducted. 166 people between the ages of 18 and 59 participated in the study.
After vaccination, the participants in the study were able to assess surprisingly well how strongly their immune system was positioned to fight the respective illness. This was especially true for people who had developed only a few antibodies. In fact, 71% of participants who did not feel well protected after vaccination also had a below-average immune response. “Our most notable finding is that those who felt they had not produced high levels of antibodies after vaccination were often correct in their assessment.”
By contrast, participants who assessed their immune response as good were not always right. However, all of those who had a particularly strong immune response also reported feeling well protected.
Alternative interpretations
For Stephanie Dimitroff, however, it is still too early to draw any final conclusions. The psychologist is considering other possible causes, including the placebo effect. This is because communication between the brain and the immune system runs in both directions. The signals from our brain can therefore also influence our immune system. People who firmly believe in vaccination or are basically optimistic could thus actually develop a better immune defence (placebo effect) and also feel better protected. It is therefore possible that belief in the effectiveness of a vaccine is what improves its efficacy, and this could also explain the high accuracy of the self-assessments.
“Our results suggest that it is quite likely that people have a real ability to assess their own health. However, I cannot rule out that there is a combination of effects at play, including the placebo effect and/or feelings of optimism,” Dimitroff says. In her view, it would make sense to repeat the study in order to confirm the results and rule out alternative causes.
The thymus gland, which produces immune T cells before birth and during childhood, is often regarded as non-functional in adults, and is sometimes removed during cardiac surgery for easier access to the heart and major blood vessels. New research led by investigators at Massachusetts General Hospital (MGH) and published in the New England Journal of Medicine has uncovered evidence that the thymus is in fact critical for adult health generally and for preventing cancer and perhaps autoimmune disease.
To determine whether the thymus provides health benefits to adults, the team evaluated the risk of death, cancer, and autoimmune disease among 1146 adults who had thymectomy during surgery and among 1146 demographically matched patients who underwent similar cardiothoracic surgery without thymectomy. The scientists also measured T cell production and blood levels of immune-related molecules in a subgroup of patients.
Five years after surgery, 8.1% of patients who had a thymectomy died compared with 2.8% of those who did not have their thymus removed, equating to a 2.9-times higher risk of death. Also during that time, 7.4% of patients in the thymectomy group developed cancer compared with 3.7% of patients in the control group, for a 2.0-times higher risk.
“By studying people who had their thymus removed, we discovered that the thymus is absolutely required for health. If it isn’t there, people’s risk of dying and risk of cancer is at least double,” says senior author David T. Scadden, MD, director of the Center for Regenerative Medicine at MGH and co-director of the Harvard Stem Cell Institute. “This indicates that the consequences of thymus removal should be carefully considered when contemplating thymectomy.”
In an additional analysis involving all patients in the thymectomy group with more than five years of follow-up, the overall mortality rate was higher in the thymectomy group than in the general U.S. population (9.0% vs 5.2%), as was mortality due to cancer (2.3% vs 1.5%).
Although Scadden and his colleagues found that the risk of autoimmune disease did not differ substantially between the thymectomy and control groups as a whole in their study, they observed a difference when patients who had infection, cancer, or autoimmune disease before surgery were excluded from the analysis. After excluding these individuals, 12.3% of patients in the thymectomy group developed autoimmune disease compared with 7.9% in the control group, for a 1.5-times higher risk.
In the subgroup of patients in whom T cell production and immune-related molecules were measured (22 in the thymectomy group and 19 in the control group, with an average follow-up of 14.2 postoperative years), those who had undergone thymectomy had consistently lower production of new T cells than controls and higher levels of pro-inflammatory molecules in the blood.
Scadden and his team now plan to assess how different levels of thymus function in adults affect individuals’ health. “We can test the relative vigour of the thymus and define whether the level of thymus activity, rather than just whether it is present, is associated with better health,” he says.
A study published in the journal Neuron has revealed the existence of a circuit in the brain that senses and regulates the anti-inflammatory response, including the triggering of behaviours associated with sickness and releasing cortisone, a potent negative regulator of immune responses. This circuit embodies a two-way connection between the brain and immune system.
Whenever infections or injuries occur, the immune system is triggered to control the infection and repair damaged tissue. This process involves the release of pro-inflammatory mediators that inform the brain of the body’s immune status and coordinate the immune response. In response to this signal, the brain sets off a complex reaction known as ‘sickness behaviour’ whose purpose is to reassign energy to the body’s different systems. This state is associated with behavioural changes including social avoidance and lethargy, metabolic adjustments such as fever and loss of appetite, and the release of hormones such as cortisone, to increase resistance to infection while also regulating immune responses.
In this study, a multidisciplinary group consisting of neurobiologists and immunologists from the Institut Pasteur, Inserm and the CNRS discovered a novel circuit used by the brain to measure inflammation levels in the blood and, in response to this, regulate inflammation. A region of the brainstem known as the vagal complex directly detects levels and types of inflammatory hormones in the bloodstream. This information is then relayed to neurons in another region of the brainstem called the parabrachial nucleus, which also receives information related to pain and certain aversive or traumatic memories. In turn, these neurons activate neurons in the hypothalamus leading to a rapid increase in cortisone in the blood.
The scientists used state-of-the-art neuroscience approaches to identify this circuit, which enabled them to individually observe the neurons involved during inflammation. The experts observed how the activity of specific neurons in the parabrachial nucleus could regulate the production of white blood cells involved in the immune response. “This research demonstrates that neural activity in the brain alone can have a powerful effect on the development of immune responses during infection or injury. It therefore provides a clear example of the powerful two-way connection between the body and brain. It also fuels our ambition to discover the impact of our brain on the way we interact with microbes, fight off pathogens and heal wounds,” explains Gérard Eberl, Head of the Institut Pasteur’s Microenvironment and Immunity Unit.
The discovery of this circuit opens up new opportunities for research that will jointly contribute to the fields of neurobiology and immunology: “This study gives us additional tools to better understand the impact of systemic inflammation on our brain, mood and on certain neurodegenerative processes,” adds Gabriel Lepousez, a neurobiologist in the Perception and Memory Unit (Institut Pasteur/CNRS).
Given the established role of the parabrachial nucleus in aversive memory processes, potential infectious threats could be averted if this circuit is reactivated by the memory of past inflammatory or aversive experiences. Drawing on this neuro-immune communication, the immune system could therefore benefit from the brain’s ability to predict and anticipate threats in our environment.
One common symptom of infection is wasting, the loss of fat and muscle. Salk scientists wanted to know whether wasting was beneficial in fighting infections. Researchers discovered the wasting response to T. brucei infection in mice occurs in two phases, each regulated by different immune cells. While fat loss did not benefit the fight against infection, muscle loss did – a surprising clue that some wasting may help manage illness.
The findings, published in Cell Reports, can inform the development of more effective therapeutics that spare people from wasting and increase our understanding of how wasting influences survival and morbidity across infections, cancers, chronic illnesses, and more.
“We often make assumptions that conditions like wasting are bad, since they often coincide with higher mortality rates,” says senior author Ayres. “But if instead we ask, what is the purpose of wasting? We can find surprising and insightful answers that can help us understand the human response to infection and how we can optimise that response.”
Defending the body from an invader requires a lot of energy. Prior studies suggested this immune-related energy consumption had the unfortunate consequence of wasting. But Ayres and team were curious to know whether wasting could be beneficial and not just a side effect.
T cells are slow to respond to infections, but when they do respond, they adapt to fight the particular infection. Ayres was interested to know whether it was these T cells causing wasting. If T cells are responsible for the condition, that would indicate wasting is not simply an unproductive side effect of energy-hungry immune cells.
The cells of interest are called CD4+ and CD8+ T cells. CD4+ T cells lead the fight against infection and can promote the activity of CD8+ T cells, which can kill invaders and cancerous cells. The two T cell types often work together, so the researchers hypothesised their role in wasting may be a cooperative effort, too.
To work out the relationship between CD4+ and CD8+ T cells and wasting, the researchers turned to the parasite T. brucei. Because T. brucei lives in fat and can block the adaptive immune response (which includes T cells) it was a perfect model infection for their questions about fat wasting and how T cells mediate that process.
The team investigated 1) the role of CD4+ and CD8+ T cells during T. brucei infection and 2) how removing CD4+ and CD8+ T cells changed the longevity, mortality rates, parasite symptoms, and amount of parasite present in infected mice.
The researchers found that CD4+ T cells acted first and initiated the process of fat wasting. Afterward, but completely independently of the fat wasting, CD8+ T cells initiated the process of muscle wasting. The CD4+ T cell-induced fat wasting had no impact on the ability for the mice to fight T. brucei or to survive infection. The CD8+ T cell-induced muscle wasting, however, contrary to the traditional assumptions about wasting, helped the mice fight T. brucei and survive the infection.
“Our discoveries were so surprising that there were times I wondered if we did something wrong,” says first author Samuel Redford. “We had striking results that mice with fully functioning immune systems and mice without CD4+ T cells lived the same amount of time – meaning, those CD4+ T cells and the fat wasting they caused were completely disposable in fighting the parasite. And beyond that, we found that normally cooperative T cell subtypes were working totally independently of one another.”
The findings illustrate the important role of immune cells in both fat and muscle wasting and the necessity to understand the function of such responses to inform therapeutic interventions.
“We can learn so much about our immune systems by looking at the environments and infections we have co-evolved with,” says Ayres. “While T. brucei is an interesting and important case, what is exciting is extrapolating our findings to understand, treat, and overcome any disease that involves immune-mediated wasting – parasites, tumours, chronic illnesses, and so much more.”
In the future, the team will examine the T cell mechanism in other mammals and eventually humans. They also want to explore in more detail why muscle wasting is occurring and why CD4+ and CD8+ T cells play these distinct roles.
Researchers have discovered that the immune cells guarding the healthy human cornea from pathogens and inflammation are T cells, and dendritic cells, as previously thought. The discovery, published in PNAS, redefines current understanding of the immune cell landscape in the cornea of a healthy human eye. It builds on the team’s previous research in Cell Reports that showed that T cells protect the eye against virus infection in mice.
The collaborative research team jointly developed a new imaging technique as part of their investigation.
Research leader Professor Scott Mueller, from the Department of Microbiology and Immunology at the Doherty Institute explained that our knowledge of the various immune cell types in the human cornea is important for establishing the eye’s protective mechanisms against pathogens and disease.
“By combining our newly developed imaging technique with other advanced analytical approaches, we were able to discover that a significant number of cells at the surface of the healthy cornea are actually T cells,” said Professor Mueller.
“Until now, these cells were mistakenly classified as dendritic cells based on static imaging. This completely changes the current dogma in the field that only dendritic cells are present in the healthy cornea.”
The study’s first author, University of Melbourne’s Associate Professor Laura Downie said that being able to dynamically capture the cells’ normal behaviour, and in response to inflammation, provides unique understanding into the immune response in the eye.
“Using our non-invasive imaging approach, which we term Functional In Vivo Confocal Microscopy (Fun-IVCM), we have been able to see that these T cells move around quickly and interact with other cells and nerves in the outermost layer of the cornea. We also captured different cell dynamics in response to contact lens wear and in allergic eye disease, and quantified how these behaviours are modulated by drug treatments,” said Associate Professor Downie.
“These findings reshape our understanding of the distinct immune cell subsets in the human cornea, and how they respond to different stimuli. Using Fun-IVCM, we can achieve rapid, real-time insight into the cellular immune responses in living humans, in this accessible peripheral sensory tissue.”
Senior author Dr Holly Chinnery, also of the University of Melbourne, added that the new research will have major implications for the medical and immunology fields, including for patients and practitioners.
“Because this new technique involves non-invasive, time-lapse imaging of the human cornea, Fun-IVCM could be used in clinics directly to assess immune responses and ocular health. It could even be used for general immune system health,” said Dr Chinnery.
“Changes in T cells and behaviour could be used as a clinical biomarker of disease and assist with treatments.”
