License to kill

A new study by Weizmann Institute of Science scientists shows that the elite units of the immune system - killer T cells - also employ a dual strategy, and include two different types of "soldier cells"

The immune system is characterized by a strong and vigorous reaction capacity against foreign invaders such as bacteria, viruses and also transplanted organs, and under certain conditions even against types of cancer cells. At the same time, it operates a strategy aimed at preserving the ability to defend itself over time - by creating an "immune memory" against these factors. A new study by Weizmann Institute of Science scientists shows that the elite units of the immune system - killer T cells - also employ a dual strategy, and they include two different types of "soldier cells": one kills the target cells by secreting the deadly protein perforin, while The second one specializes in killing target cells by activating receptors that cause the target cell to "lose itself knowing" by activating the apoptosis mechanism - without any secretion of toxic substances.

The ability of Cytotoxic T Lymphocytes (CTL) to kill other cells underlies several essential immune responses. These cells know how to locate and attack the invaders hiding in our body. Among these are cells that have been taken over by viruses or bacteria, and even cancer cells that masquerade as normal cells to escape the immune system's attack. It is the attacks of T cells that kill foreign cells that cause recovery from a viral infection such as the flu, but also the unwanted phenomenon of transplant rejection.

Their overactivity can cause damage and even autoimmune diseases. In other cases, body tissues infected with viruses are partially damaged without the virus being completely destroyed, as in chronic viral hepatitis. Insufficient activity of killer T cells can lead to the development of diseases, and sometimes even to cancer. Prof. Gideon Barka from the Department of Immunology at the Weizmann Institute of Science, one of the research pioneers in the field, has been researching the T-cells that kill for more than 40 years. His research was summarized in the book Killer lymphocytes written in partnership with Prof. William R. Clark, and was published by Springer.

The first hypothesis regarding the molecular killing mechanism of killer T cells was put forward by Pierre Hankart from the US National Institutes of Health (NIH). Hankart discovered that T cells destroy their target cells by secreting a deadly protein called perforin, and suggested that the protein creates holes in the target cell's membrane, thereby causing its death. In the studies of Prof. Barka and Dr. Dalia Rosen, no evidence of this was found, but evidence was discovered for a new alternative mechanism, which does not involve the secretion of perforin, but is conducted as a kind of "Krav Maga" between receptors displayed on the membranes of the killing T cells and those expressed on the target cells. The link between a molecule displayed on the membrane of the T cell (called FasL) and the death receptor displayed on the membrane of the target cell (FAS) - discovered by the Japanese Prof. Shigetsu Nagata and the German Prof. Peter Kramer - constitutes the "pull of the trigger" that causes its death of the target cell. It later turned out that the two scientific teams were right, and that the two killing mechanisms work side by side. Both are based on the same mechanism for identifying the target cells, and both mechanisms have one result - the death of the target cell. So, why do the T-cells that kill two different killing mechanisms need, and what is their origin?

This question was the focus of Prof. Barka's current research, which was recently published in the journal of the British Immunology Association (Immunology), in which research students Avihai Mirez and Shaul Harari, Dr. Orit Gal Garber, and Dr. David Hassin from the Tel Aviv Medical Center participated. Aviv named after Sourasky, who stayed in Barka's laboratory as part of a sabbatical year. The team members used a model that allows tracking the activity of the killer T cells during graft rejection of a cancerous tumor. The rejection response leads to the death of the transplanted cells, and killer T cells remain at the scene. The research findings show that the two killing mechanisms are activated at different intensities throughout the immune response, complement each other, and serve different purposes: immediately upon exposure to transplanted cells, the killing mechanism by means of perforin begins to operate, which is faster and more aggressive. Most of the killer T-cells found on the battlefield used this mechanism, and their quantity reached a peak at the time of rejection of the graft - about a week after its insertion. Along with the death of the tumor cells, many of the killer T cells also died - a well-known phenomenon, which aims to prevent destructive overactivity of the immune system. Later, killer T cells lacking perforin, which use the FasL mechanism, were found on the battlefield. These cells maintain their destructive activity over time and can be detected even a month or more after the rejection, and they play a role in controlling the immune response.

Prof. Barka: "The work closes a circle, and proves the bi-mechanistic cellular basis for the various killing processes that have been discovered. The existence of alternative and complementary mechanisms is a characteristic phenomenon of the immune system, which is a dynamic system that undergoes processes of maturation, change and preservation (memory) in order to adapt itself to the body's needs: to get rid of cells infected with viruses or foreign agents as quickly as possible, and then to create a continuous state of guarding immune activity. In a broader aspect, the two types of killer T cells, which use two different attack strategies, allow covering a wide range of challenges and dealing with viruses, with bacteria, and even with cancerous tumors that have developed methods of evading one of the killing mechanisms."

The research findings may improve the ability of doctors to assess the chances of transplanted organs being accepted after the transplant, since the currently accepted prediction - based mainly on the presence of perforin-producing cells in the biopsy taken from the transplanted organ - is not accurate enough. Prof. Barka believes that a test that will also include the identification of the cells that use the FasL mechanism will be a complementary measure for evaluating the strength of the immune response activated against the transplanted organ, and will help determine the necessity of anti-rejection drugs.