How many cells does it take to produce memory?

Before the starting whistle of ball games, the players usually gather in a circle and divide the roles on the field between them. A new study by scientists at the Weizmann Institute of Science shows that even cells of the immune system gather before they go on a campaign against an invader, and decide together what role each one will play: some will participate in a short-term attack, while others will contribute to the creation of immune memory, which will lead to long-term resistance against future infections. The research findings thatwere published recently in the scientific journal Science, may enable the development of better vaccination strategies, including for diseases for which there is currently no effective vaccine.

In the study, the researchers examined the behavior of "helper T cells" after identifying a foreign factor. Prof. Nir FriedmanThe Department of Immunology explains that helper T cells are the ones that direct the activity of the various cells that participate in the immune response - B cells that produce antibodies, macrophages that "eat" bacteria, and also "killer T cells", which poison infected cells and kill malignant cells. When a foreign invader (e.g. a virus or bacteria) enters the body, helper T cells recognize the presence of a pathogen - a process that occurs in the lymph nodes - and in response divide into a large number of daughter cells and organize to fight the invaders. Most of the daughter cells become "active cells" (effector cells) which take part in the attack and die shortly after. But cell differentiation also produces memory cells, which remain in the body for years or even decades, and protect us from repeated attacks by the same pathogen. In recent years, it was discovered that T cells cluster together and form clusters within the lymph nodes, but it was not clear what the significance of these findings was. The new research reveals that this clustering is essential for the activity of the immune system: the clustered cells communicate with each other, count the cells in their immediate environment at any given moment, and decide together how to continue the differentiation process.

The members of Prof. Friedman's group, led by Dr. Michal Polonsky, who was at the time a research student in the laboratory, and in collaboration with the research group of Prof. Benjamin Chain From UCL University in London, we examined the question of whether the T-cell clusters, previously observed by Prof. Friedman and others, play any role in the immune response and in particular in the formation of memory cells. To answer the question, the scientists turned to a method previously developed in Prof. Friedman's laboratory: growing cells in "microbars" - surfaces containing thousands of niches smaller than the thickness of a hair - and monitoring the growth and development of these cells for several days.

At the beginning of the experiment, only one or two T cells were inserted into some of the "micro-bars", while a larger number were inserted into other "bars" - up to ten cells per "bar". After activating the T cells (in a process that simulates the recognition of a foreign invader entering the body), the researchers followed the division, differentiation and clustering of the cells under a microscope. The two types of cells - the active cells and the memory cells - were coded in different colors to facilitate identification.

The researchers found a significant difference between the "wells" in which single helper T cells were seeded and the "wells" where the initial conditions were denser: in the denser "wells" more memory cells were formed. The analysis of the data revealed that the cells can "function" - a phenomenon reminiscent of the "quorum sensing" known among bacteria: using various environmental cues, the bacteria quantify the size of the colony and use the information to make decisions that affect the entire colony. "In the case of T cells, the process is more complex," says Prof. Friedman. "There is a collective decision-making process here. The T cells do not make the decision to become memory cells by themselves, independently, but 'consult' with their neighbors and decide jointly. The greater the number of T cells, the faster and more efficient the differentiation to create memory cells."

During the experiment, the research team was able to isolate some signaling molecules secreted by the congregating T cells, and showed how these help the cells "sense" the size of the group and produce more or less memory cells as a result. Says Prof. Chain: "The immune system needs to allocate resources efficiently. Once there are enough T cells to fight the infection, she can afford to turn the remaining ones into memory cells that will allow her to fight the invaders at a later time."

The vaccines that exist today are designed to allow the body to produce memory cells, through a standard process of differentiation: they expose the body to a dead or weakened pathogen and thus activate the T cells in the lymph nodes which begin to divide and differentiate as if they were facing a real threat. "We may be able to use this knowledge to bias the immune response so that more memory cells are formed at the expense of an immediate immune response," says Prof. Chein. "The findings may also help in the development of new vaccines for diseases that currently have no way to prevent them, or vaccines adapted to the elderly whose immune systems are weakened, and may even lead to new directions in the cancer vaccine," adds Prof. Friedman.

London-Rehovot axis

Since they first met about ten years ago, Prof. Benjamin Chain from UCL University in London spends a month a year in Prof. Friedman's laboratory at the Weizmann Institute of Science. During this decade, the laboratories exchanged students and ideas with each other - a collaboration made possible, among other things, thanks to the program Making Connections which was founded on the initiative of the British Committee of the Friends of the Weizmann Institute of Science. Already in the eighties of the last century, Prof. Chein identified clusters of immune system cells, called dendritic cells, but he did not have the necessary research tools at his disposal to find out what caused them. "Only by using today's advanced methods, and thanks to the collaboration between the two laboratories, can we really study these aggregations at the single cell level and over time."