The Cleanup Crew in Your Bloodstream

In the past, immune cells were all simply known as white blood cells. Nowadays, we know that there are T cells, B lymphocytes, macrophages, autoreactive T helper cells, microglia, Tregs and others. Together, they form a team that patrols the body like a health police force, keeping harmful pathogens in its sights. These include, for example, viruses or harmful bacteria, as well as fungi, parasites, cancer cells and toxins. Some of them produce antibodies, while others trigger defense mechanisms or perform tasks like devouring, cleansing or disposing of waste, and calming the system. They can even go into a state of shock-induced paralysis.

“However, we still don’t fully understand which situations cause the immune system to react in what way. That’s where things get interesting,” says UZH immunologist Nicole Joller, who wrote her thesis in the group led by experimental immunologist Rolf Zinkernagel. He was awarded the Nobel Prize in Physiology or Medicine in 1996 for his discovery of how the immune system recognizes virus-infected somatic cells. 

Nicole Joller’s research focus is the regulation of the immune system. And when it comes to regulation, the devil is in the details, she says with a wink. Why doesn’t the immune system always work properly? Why, in autoimmune diseases, does the immune system launch an attack instead of providing protection? Why does it react so excessively in the case of allergies? Why doesn’t it eliminate cancer cells effectively, instead allowing them to proliferate? Joller’s team is currently studying the “brakes” of the immune system: regulatory T cells (Tregs). Tregs are the balancing forces that maintain equilibrium between the body’s defenses against infections and its self-protection mechanisms. They do this by stopping “improperly trained” T cells that escape from their “nursery”, the thymus, and then attack the body’s own cells in the tissues as if they were foreign bodies.

It took three decades and much controversy before the hypothesis that regulatory T cells exist could be proven. The Nobel Prize was awarded for this discovery in 2025. “This shows how important the immune system’s brakes are – and, of course, gives our research group a tremendous boost,” says Joller. Tregs are also of interest to clinicians. They can do more than just put on the brakes: “Certain functions of the immune system can be switched off, while others continue to operate,” explains Joller. This makes targeted immunotherapies possible. These therapies don’t paralyze the immune system (as chemotherapy has done until now) but instead specifically reactivate the immune defenses that have been circumvented by the tumor.

Joller’s group aims to determine which of the immune system’s brakes need to be active and when in order to keep the body healthy. From an immunological standpoint, this means achieving a balance between the body’s defenses and its self-protection mechanisms. Starting with the healthy immune system, the researchers set out to investigate what goes wrong in diseases such as cancer, allergies and autoimmune disorders such as multiple sclerosis (MS).

Neurologist Roland Martin and immunologist Mireia Sospedra have been collaborating on MS research for 20 years, working both at UZH and their spin-off, Cellerys. In MS, misdirected T and B cells travel from the bloodstream to the central nervous system, where they attack the nerve fibers’ natural protective sheath (myelin) as if it were a foreign pathogen. This triggers a damaging inflammatory response.

“If you were diagnosed with MS in the 1980s, there wasn’t much doctors could do,” Martin recalls. Patients had to accept that, within 10 or 20 years, they would be confined to a wheelchair. Today, there are over twenty medications that can largely stabilize newly diagnosed patients and help them lead a “normal” life. “When a patient is diagnosed with MS, most of the time we can almost promise that they’ll never become seriously disabled,” Martin says. 

Thanks to new methods and discoveries, several of which have been awarded Nobel Prizes, it is now possible to study highly complex processes in the body. “Ten years ago, this would have been unthinkable,” says Martin, who, even after retiring, continues to research the neuroimmunology of MS – successfully and with enthusiasm. “It’s incredibly satisfying when you come to understand mechanisms that were initially considered very complex, or when you discover new treatments – or even help make such discoveries possible.”

In the late 1990s, Roland Martin and his team began developing an immune tolerance therapy for MS. The idea behind it is to “re-educate” the misdirected T cells so that they no longer attack the body’s own myelin. Early studies showed that tolerance-induced therapy is highly safe. It specifically reduces the harmful immune response and leaves the rest of the immune system unaffected.

Roland Martin and Mireia Sospedra are currently focusing on the connections between the immune system and other bodily functions. “In the past, the immune system was viewed rather one-dimensionally as a factory producing antibodies to fight invaders,” says Martin. Now, it’s becoming increasingly clear that it is in fact intricately interwoven with the entire body. In the past, the bone marrow, thymus, spleen and lymph nodes were known as the “central hubs” of the immune system. Today, we know that the brain, the skin and the mucous membranes of the nose, throat, bladder and genitals also play important roles, as do vitamins, beneficial bacteria, hormones, metabolic intermediates, waste products (metabolites), and much more. And above all, we know the importance of the gut.

For an effective defense against pathogens, the microorganisms in the gut, the intestinal epithelium and the immune system in the mucous membranes are all essential. About 80% of the body’s immune cells are found in the gut. For MS researcher Mireia Sospedra, the discovery that the gut plays a crucial role in immune response is incredibly inspiring. For example, a microbiome study from UZH and University Hospital Zurich showed that gut bacteria can mobilize the immune system when cancer develops. They rouse T cells from their state of shock, allowing them to once again fight cancer cells misidentified as harmless.

What could this mean for MS? Sospedra pondered this question in light of two observations from research. Firstly, high concentrations of antibodies (IgG) versus components of the gut bacterium Akkermansia muciniphila are found in the cerebrospinal fluid of MS patients. And secondly, children and young adults who are obese are more likely to develop MS than their healthy-weight peers – and this is true to a greater extent in this age group than it is for adults.

Sospedra wondered whether gut bacteria also play a role in the development of MS. It’s certainly possible, she says, and goes on to outline a potential explanation. In healthy individuals, the gut bacterium Akkermansia muciniphila contributes to metabolic health. It feeds on the body’s own intestinal mucus (mucin) and, in doing so, stimulates the continuous renewal of this protective layer. When children and adolescents eat only low-fiber junk food, many beneficial bacteria in their gut, which rely on fiber-rich foods, begin to wither away. When the microbiome changes, mucus production also becomes unbalanced. At some point, Akkermansia muciniphila starts digesting more intestinal mucus than can be replenished. Ultimately, the protective layer becomes so thin that it is susceptible to inflammation.

Once inflammation sets in, things start to go downhill. Certain T cells are activated that recognize the gut bacterium responsible for triggering the inflammation. Activated T cells – the only immune cells capable of this function – cross the blood-brain barrier to enter the central nervous system (CNS), where they search for the agents causing inflammation. In people with MS, they also cross a second barrier into the brain, the glia limitans. If they encounter the same protein from Akkermansia muciniphila that activated them in the gut in the CNS, they attack the tissue. “In some patients, inflammation caused by poor diet and an imbalance of gut bacteria may play a role in the development of MS,” Sospedra suggests. 

Through their research, Roland Martin and Mireia Sospedra have identified several of the proteins that tend to be attacked by misdirected T lymphocytes. “But not yet all of them, and we also don’t know whether they’re always the same in every patient,” says Sospedra. They have also discovered several MS autoantigens, as well as antigens that should specifically be protected from damage. The causes of MS have not yet been fully understood. There is, however, growing evidence to support the idea that, in addition to immunologically relevant genetic variants and certain viruses (such as the Epstein–Barr virus), “bad” bacteria in the gut microbiota, low vitamin D levels, and the toxins in cigarette smoke also significantly increase the risk of disease. Further basic research is needed to shed light on these connections. 

Those who conduct basic research shouldn’t feel discouraged when things don’t quite go as expected. Experimental immunologist Nicole Joller has made it her method to systematically investigate unexpected research findings – ones she didn’t anticipate – using mouse models and lab work. Like a detective, she sets out to uncover the underlying causes. This is how her research group discovered the “switch” molecules that, during inflammation, either activate or inhibit regulatory T cells (Tregs) – much like the control lever on a tram. “In allergies, the brake function fails,” Joller explains. “In tumors, ‘switch’ molecules fail to stimulate the immune response enough.”

When the research group noticed, to their surprise, that the tissue and well-being of the mice they were studying were improving, even though the virus was still present in their bodies, they also investigated this unexpected finding. And they discovered that the “switch” molecule also triggers a repair function in the immune system. “The immune system also functions like a cleanup crew and a repair shop, helping the body maintain homeostasis – in other words, balance,” explains Joller.

Gradually, the overall picture becomes clearer with each new piece of the puzzle added by basic researchers: “The immune system plays a crucial role in ensuring that all parts of the body, including cognitive function, tissue repair and energy management, remain stable despite changing environmental influences. This is still often underestimated,” says Joller.