Newly Discovered Molecular Mechanism Offers Perspectives on Targeting Autoimmune Diseases

19 Apr 2017 --- Scientists of the Luxembourg Institute of Health (LIH) have discovered a so far unknown molecular mechanism by which the human immune system activates its immune cells: T cells, a particular type of white blood cells, effectively ward off pathogens if a gene known as Gclc is expressed within them. The Gclc gene encodes a protein instrumental for the production of a substance called glutathione – a molecule that was previously known only to eliminate harmful waste products of metabolism such as reactive oxygen species and free radicals.

A team led by LIH researcher Prof Dirk Brenner, FNR ATTRACT fellow and Head of the Experimental & Molecular Immunology research group at the Department of Infection and Immunity, has discovered that glutathione also stimulates T cells’ energy metabolism. This way, when in contact with pathogens, T-cells can grow, divide and fight off intruders such as viruses. Glutathione is thus an important molecular switch for the immune system. This discovery offers starting points and perspectives to develop new therapeutic strategies for targeting cancer and autoimmune diseases.

The scientists publish their findings yesterday in the world’s most prestigious immunology journal, Immunity.

“Our body has to keep our immune system in a carefully balanced equilibrium,” Prof Dirk Brenner says. “If the body’s innate defenses are overactive, then they turn against the body. This is what happens in autoimmune diseases like multiple sclerosis or arthritis, for example. However, if the defenses are too weak, then infections cannot be handled or body cells can proliferate uncontrolled and grow to form tumors, which can become life threatening.”

Immune cells such as T cells therefore normally reside in a state of alert hibernation, with their energy consumption reduced to a minimum. If pathogens or parts thereof dock onto their outer envelope, then the T cells wake up and boost their metabolism. This necessarily creates greater amounts of metabolic waste products, such as reactive oxygen species (ROS) and free radicals, which can be toxic for the cells.

When the concentration of these oxidants increases, the T cells have to produce more antioxidants so as not to be poisoned. No previous research group had studied the mechanism of action of antioxidants in T cells to great detail before. In exploring this phenomenon, Prof Brenner’s team discovered that the antioxidant glutathione produced by T cells serves not only as a garbage collector to dispose of ROS and free radicals, it is also a key switch for energy metabolism that controls the immune response, and is thus of high relevance to various diseases.

“These fascinating results form a basis for a targeted intervening in the metabolism of immune cells and for developing a new generation of immunotherapies,” explains Prof Markus Ollert, Director of LIH’s Department of Infection and Immunity.

For their investigations, the scientists employed genetically modified mice in whose T cells the Gclc gene was removed and therefore these cells could not produce glutathione.

“In these mice, we discovered that the control of viruses is impaired – mice that lack the Gclc gene have an immunodeficiency. But by the same token, this also meant the mice could not develop any autoimmune disease such as multiple sclerosis,” Brenner says.

Further tests performed by Prof Brenner’s team demonstrated the reason for this: “The mice cannot produce any glutathione in their T-cells,” Brenner continues, “and so a number of other signaling events that directly boost metabolism and increase energy consumption are lacking.” As a result, without glutathione, T-cells do not become fully functional; they remain in their state of hibernation and no self-destructive autoimmune response occurs.

Prof Karsten Hiller from the Braunschweig University of Technology, who collaborated with the Luxembourgish scientists, adds: “It is intriguing to see that cellular metabolism and immune activation are so tightly entangled and that a fine-grained interplay is essential to achieve a correct function."

Prof Brenner sees his T cell experiments as a prelude to more in-depth investigation of the energy balance of immune cells in general. A number of different autoimmune diseases, for example, are related to malfunctions in various subgroups of T cells. “If we understand the differences in the molecular mechanisms by which they stimulate their metabolism during defensive or autoimmune responses, then we can discover clues as to possible attack points for therapeutic agents regulating the immune response.” The distinguished researcher sees a similar situation in cancer: “In this context too, it is important to know why the immune cells that are actually supposed to fight cancer cells drop to a low metabolic state and in some cases even actively suppress an immune response against the tumor. Counteractive metabolism-stimulating measures could make the immune cells work more efficiently and fight off cancer more effectively.”

In follow-up projects, the researchers are planning to gain new indications for potential sites of therapeutic interventions. The groups from Luxembourg and Braunschweig are currently applying for new research funding for a joint project supported by the German Research Foundation (DFG) and the Luxembourg National Research Fund (FNR).

A team led by LIH researcher Prof Dirk Brenner, FNR ATTRACT fellow and Head of the Experimental & Molecular Immunology research group at the Department of Infection and Immunity, has discovered that glutathione also stimulates T cells’ energy metabolism. This way, when in contact with pathogens, T-cells can grow, divide and fight off intruders such as viruses. Glutathione is thus an important molecular switch for the immune system. This discovery offers starting points and perspectives to develop new therapeutic strategies for targeting cancer and autoimmune diseases.

The scientists publish their findings yesterday in the world’s most prestigious immunology journal, ***Immunity.

“Our body has to keep our immune system in a carefully balanced equilibrium,” Prof Dirk Brenner says. “If the body’s innate defenses are overactive, then they turn against the body. This is what happens in autoimmune diseases like multiple sclerosis or arthritis, for example. However, if the defenses are too weak, then infections cannot be handled or body cells can proliferate uncontrolled and grow to form tumors, which can become life threatening.”

Immune cells such as T cells therefore normally reside in a state of alert hibernation, with their energy consumption reduced to a minimum. If pathogens or parts thereof dock onto their outer envelope, then the T cells wake up and boost their metabolism. This necessarily creates greater amounts of metabolic waste products, such as reactive oxygen species (ROS) and free radicals, which can be toxic for the cells.

When the concentration of these oxidants increases, the T cells have to produce more antioxidants so as not to be poisoned. No previous research group had studied the mechanism of action of antioxidants in T cells to great detail before. In exploring this phenomenon, Prof Brenner’s team discovered that the antioxidant glutathione produced by T cells serves not only as a garbage collector to dispose of ROS and free radicals, it is also a key switch for energy metabolism that controls the immune response, and is thus of high relevance to various diseases.

“These fascinating results form a basis for a targeted intervening in the metabolism of immune cells and for developing a new generation of immunotherapies,” explains Prof Markus Ollert, Director of LIH’s Department of Infection and Immunity.

For their investigations, the scientists employed genetically modified mice in whose T cells the Gclc gene was removed and therefore these cells could not produce glutathione.

“In these mice, we discovered that the control of viruses is impaired – mice that lack the Gclc gene have an immunodeficiency. But by the same token, this also meant the mice could not develop any autoimmune disease such as multiple sclerosis,” Brenner says.

Further tests performed by Prof Brenner’s team demonstrated the reason for this: “The mice cannot produce any glutathione in their T-cells,” Brenner continues, “and so a number of other signaling events that directly boost metabolism and increase energy consumption are lacking.” As a result, without glutathione, T-cells do not become fully functional; they remain in their state of hibernation and no self-destructive autoimmune response occurs.

Prof Karsten Hiller from the Braunschweig University of Technology, who collaborated with the Luxembourgish scientists, adds: “It is intriguing to see that cellular metabolism and immune activation are so tightly entangled and that a fine-grained interplay is essential to achieve a correct function."

Prof Brenner sees his T cell experiments as a prelude to more in-depth investigation of the energy balance of immune cells in general. A number of different autoimmune diseases, for example, are related to malfunctions in various subgroups of T cells. “If we understand the differences in the molecular mechanisms by which they stimulate their metabolism during defensive or autoimmune responses, then we can discover clues as to possible attack points for therapeutic agents regulating the immune response.” The distinguished researcher sees a similar situation in cancer: “In this context too, it is important to know why the immune cells that are actually supposed to fight cancer cells drop to a low metabolic state and in some cases even actively suppress an immune response against the tumor. Counteractive metabolism-stimulating measures could make the immune cells work more efficiently and fight off cancer more effectively.”

In follow-up projects, the researchers are planning to gain new indications for potential sites of therapeutic interventions. The groups from Luxembourg and Braunschweig are currently applying for new research funding for a joint project supported by the German Research Foundation (DFG) and the Luxembourg National Research Fund (FNR).

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