The memory of the immune system

Immune defences are at the heart of our ability to respond to disease, but how does the system that protects us every day actually function? Professors Federica Sallusto, director of the Cellular Immunology Laboratory at the USI-affiliated Institute for Research in Biomedicine (IRB), and Antonio Lanzavecchia, who served as the founding director of the institute from 2000 to 2020, explained this in a piece written in collaboration with laRegione to commemorate the IRB's 25th anniversary.

Imagine being able to perfectly remember every person you have ever met, recognising them even decades later and responding accordingly. This is similar to how our immune system operates through a remarkable mechanism known as immunological memory. This ability allows the immune system to "remember" pathogens it has encountered before, enabling it to respond more quickly and effectively during subsequent encounters. Immunological memory is one of the most elegant evolutionary solutions for safeguarding our bodies against microbial threats. It helps us respond more efficiently to familiar enemies and serves as the foundation for how vaccines function.

Early historical observations: from Thucydides to Jenner

The earliest recorded account of immunological memory can be traced back to ancient Greece. During the great plague of Athens in 430 BC, historian Thucydides made an intriguing observation: those who had recovered from the disease did not become ill a second time, even while caring for new patients. Although Thucydides could not have understood the molecular mechanisms behind this phenomenon, his insightful observation highlighted one of the fundamental characteristics of the immune system.

The next step in understanding and applying immunological memory occurred in the 18th century with the practice of variolation. This technique, which originated in China and the Ottoman Empire, involved inoculating healthy individuals with material taken from the pustules of patients with mild smallpox. However, a real breakthrough came with Edward Jenner in 1796. The English physician noticed that milkmaids who contracted cowpox, a milder form of the disease, seemed to be protected from human smallpox. Jenner conducted an experiment in which he inoculated an eight-year-old boy named James Phipps with material from cowpox. Six weeks later, he deliberately exposed James to human smallpox, and the boy did not become ill. Jenner had just demonstrated the principle of cross-protective vaccination, using a related but less virulent pathogen to induce protection against a more serious disease. The term "vaccine" derives in fact from the Latin word vacca, which means "cow.", in honour of this first practical application of immunological memory.

The biological basis: T and B lymphocytes, the guardians of memory

To understand how immunological memory works, we need to explore the microscopic world of immune system cells. The main players in this process are two types of white blood cells: T lymphocytes and B lymphocytes. B lymphocytes act as the "factories" for antibodies. When they encounter a pathogen for the first time, they become activated and transform into plasma cells, which then produce specific antibodies targeted at that particular pathogen. Antibodies are Y-shaped proteins that bind to specific parts of the pathogen, known as antigens, marking it for destruction or neutralising it directly.

On the other hand, T lymphocytes have various functions depending on their subtype. Helper T cells, for example, coordinate the immune response by communicating with other cells and assisting in the activation of B cells. Killer T cells recognise and directly destroy infected cells.

During the first exposure to a pathogen, called the primary response, the immune system takes several days to mount an effective response. It is during this period that we often experience the symptoms of the disease. However, once the pathogen has been defeated, not all activated lymphocytes die: some are transformed into memory lymphocytes. These cells persist in our bodies for years, sometimes for life, remaining in a state of "alert". When the same pathogen attempts a second invasion, the memory cells recognise it and trigger a much faster and more powerful response, called the secondary response.

Discoveries at the IRB

For decades, immunologists considered memory cells to be a homogeneous group. However, in the late 1990s, our research, which began at the Institute of Immunology in Basel and continued in Bellinzona, changed this perspective. We demonstrated that memory T lymphocytes are not all the same; instead, they can be divided into two populations, each with distinct characteristics and functions. Central memory lymphocytes serve as a strategic reserve in the lymph nodes, are characterised by a high capacity for proliferation, and can generate new effector cells when stimulated. Effector memory lymphocytes, on the other hand, are the soldiers on patrol that circulate in peripheral tissues, ready for immediate action but with a shorter lifespan. Once the two types of lymphocytes had been distinguished, research focused on understanding their roles in defence mechanisms, not only in protecting against infections, but also in responding to cancer cells and in the processes that lead to autoimmune diseases. Today, researchers are trying to understand how to stimulate these cells through vaccination to achieve more targeted and lasting protection. The role of tissue-resident memory T cells, a third population of memory cells discovered more recently, is also being studied.

At the IRB, we have developed an innovative technique to isolate human monoclonal antibodies directly from memory B cells or plasma cells. This technique enables us to capture the antibody memory developed after infections or vaccinations to produce therapeutic antibodies. It has been effective in creating monoclonal antibodies against a variety of viruses, including influenza, respiratory syncytial virus (RSV), and Ebola. During the COVID-19 pandemic, monoclonal antibodies like Sotrovimab—discovered in Bellinzona and developed by Vir Biotechnology in collaboration with GSK—provided immediate protection to high-risk patients globally.

The evolution of vaccines

The journey from Jenner's initial intuition to the advancements in modern biotechnology is a captivating story of medical innovation. Live attenuated vaccines, a direct evolution of Jenner's method, contain weakened versions of pathogens that can replicate but do not cause disease. Albert Sabin's oral polio vaccine, delivered on sugar cubes, facilitated mass vaccination campaigns that led to the near eradication of polio.

Inactivated vaccines, such as the one developed by Jonas Salk against polio, use killed pathogens that retain the ability to stimulate the immune system. Subunit vaccines represent a further evolution, containing only the essential parts of the pathogen. The hepatitis B vaccine, developed in the 1980s, was one of the first successes of this technology. In recent decades, we have witnessed a remarkable biotechnological revolution. mRNA platforms and viral vectors, like those created for COVID-19, transform our cells into temporary "factories" for producing antigens, marking a new chapter in the history of vaccines.

Current challenges and prospects

Despite significant advancements, considerable challenges still exist. Specific pathogens, such as HIV and influenza viruses, mutate rapidly, making it challenging for immunological memory cells to provide effective protection. Researchers are working to identify conserved regions of these viruses that are less prone to mutation, to develop immunity against these stable targets. The use of artificial intelligence could expedite the creation of new "universal" vaccines designed to protect against continuously evolving viruses.

One of the most challenging tasks is to understand how the immune system changes at different stages of life. In very young children, the immune system is still immature, which poses particular difficulties. A better understanding of how immunological memory develops in the early years of life is therefore essential for devising effective vaccination strategies against viruses that cause serious infections in this age group, such as the RSV virus. Conversely, in old age, the phenomenon of immunosenescence reduces the efficiency of immune responses. IRB researchers, together with researchers from the IOR and the Swiss Federal Institute of Technology in Zurich, are jointly addressing this issue as part of a large research project, NCCR Ageing, currently being evaluated by the Swiss National Science Foundation. A deeper understanding of the optimal strategies for stimulating the age-weakened immune system of the elderly would have a considerable impact not only on the optimisation of existing vaccines, but also on the development of vaccines against pathogens that cause serious infections in the elderly (including Staphylococcus and Klebsiella), as well as on the development of therapeutic anti-cancer vaccines.

A future of personalised protection

The journey from Thucydides' initial observations to the breakthroughs of the modern era is one of the greatest achievements in medicine. The COVID-19 pandemic has demonstrated the rapid response of science to health emergencies, leveraging a strong foundation of knowledge about the immune system. Looking ahead, immunological memory will remain central to our efforts to combat emerging infectious diseases, develop cancer therapies, and understand autoimmune disorders. Each discovery in this field not only enhances our understanding of human biology but also reinforces the foundations for building a more effective and personalised medicine for the future.