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A team of scientists at the Luxembourg Institute of Health (LIH), led by FNR ATTRACT Fellow Prof Dirk Brenner, have discovered a novel mechanism through which the immune system can control autoimmunity and cancer. The findings set a new direction for the development of future treatments of metabolic diseases. In a nod to the significance of the findings, the research graces the cover of the journal ‘Cell Metabolism’.

“Our immune system is needed for a healthy body function and protects us from all kinds of infections. Particularly important in this respect are T cells, and specifically regulatory T cells. Although these represent only a small fraction of all T cells, they are crucial to keep our immune system in check” explains Prof Dirk Brenner, leader of the Experimental & Molecular Immunology research group in the LIH’s Department of Infection and Immunity, where he also serves as Deputy Head of Research & Strategy.

“If regulatory T cells are not functional, the immune system gets out of control and turns against its own body. This can lead to detrimental autoimmune diseases like multiple sclerosis, type I diabetes or arthritis. However, a highly reactive immune system can kill cancer cells very efficiently. This has led to the development of ‘checkpoint inhibitors’, specific drugs that unleash an immune system attack on cancer cells and which won the Nobel Prize in Medicine in 2018”.

Focus on regulatory T-cells

The Luxembourgish scientists took this angle – focussing on regulatory T-cells and revealed a novel mechanism that can control the balance between an extreme or subdued immune reaction can be controlled by modifying regulatory T cell metabolism.

Initially, the researchers focused on how regulatory T cells cope with stress. Cellular stress can originate from the cells themselves, for example when they activate and divide, but also from their environment, especially from nearby tumour cells.

Free radicals called reactive oxygen species (ROS) are the molecular mediators of cellular stress. These are harmful for the cells and therefore need to be inactivated.

“Free oxygen radicals are ‘neutralised’ by antioxidants and the major antioxidant in T cells is a molecule known as glutathione. We were surprised when we realised that regulatory T cells had about three times as much glutathione as other T cells. This pointed to an important function”, says Henry Kurniawan, first author of the study and PhD student in Prof Brenner’s group.

Free radical accumulation and fatal autoimmune disease

Through a sophisticated genetic approach, the scientists removed took a small population of regulatory T cells in mice and removed a gene named ‘glutamate cysteine ligase’ (Gclc), which is instrumental in glutathione production.

Prof Brenner’s team discovered that free radicals accumulated in these genetically altered regulatory T cells and that these cells lost their ability to act as a brake on the immune system. Strikingly, this led to a massive immune activation and a fatal autoimmune disease.

The team also found that the absence of glutathione in regulatory T cells massively increased serine metabolism. Serine is one of the 22 different amino acids that constitute the building blocks of proteins, which are in turn important for the structure and function of cells.

No previous research group had studied the connection between glutathione, free radicals, serine and regulatory T cell function before. The team characterised the metabolic alteration that led to the observed autoimmune disease in their mutant mice.

An engineered precision diet to the rescue

Based on their findings, they designed a specific nutritional plan with the aim of correcting these disease-causing metabolic shifts. This dietary plan lacked both the amino acids serine and the closely related glycine. Interestingly, this engineered precision diet suppressed the severe autoimmunity – and no disease developed.

“Importantly, our study shows that the absence of only 2 out of 22 amino acids can cure a complex autoimmune disease. Therefore, elucidating the exact metabolic and molecular basis of a disease offers the possibility to correct these metabolic abnormalities through a special diet that is precisely adapted to the delineated disease mechanism. Our study might be a first step in the direction of the personalised treatment of metabolic diseases and autoimmunity”, explains Prof Brenner.

Findings also promising for cancer treatment avenues

“The relationship between glutathione, free radicals and serine can be used as a ‘switch’ to modulate immune cell activation. A higher immune cell activity is beneficial for cancer patients. We were intrigued by the idea of using our findings also to boost anti-tumor responses” he adds.

Indeed, the team further showed that lower glutathione levels in regulatory T cells and the resulting rise in immune cell activation led to a significant tumour rejection, which might open up new therapeutic avenues for cancer treatment.

In future projects, the researchers will use their findings to elaborate new approaches for therapeutic intervention. In that respect, the scientists have already proven that their delineated disease-controlling mechanism is also relevant in human regulatory T cells.

Publication

The publication is titled ‘Glutathione Restricts Serine Metabolism to Preserve Regulatory T Cell Function’, published in the May 2020 issue of Cell Metabolism (DOI: https://doi.org/10.1016/j.cmet.2020.03.004). Due to the significance of the findings, the publication was selected by Cell Metabolism to be featured as the cover story of the May issue of the journal. The research has also been featured in the national and international press.

An international effort

The study was performed in close collaboration with a national and international team and involved partners from LIH’s Department of Infection and Immunity, LIH’s Department of Oncology, the Braunschweig Integrated Center of Systems Biology (BRICS) of the Technische Universität Braunschweig (Germany), the Helmholtz Centre for Infection Research (Germany), the Campbell Family Institute for Breast Cancer Research at the University of Toronto (Canada), the Institute for Medical Microbiology and Hospital Hygiene at the University of Marburg (Germany), the Department of Environmental Health Sciences at the Yale School of Public Health (USA), the Odense Research Center for Anaphylaxis (ORCA) of the Odense University Hospital (Denmark), the Department of Biomedical Genetics and Wilmot Cancer Institute of the University of Rochester Medical Center (USA), the Departments of Medical Biophysics and Immunology at the University of Toronto (Canada) and the University of Hong Kong (China).

About Prof Dirk Brenner

Prof Dirk Brenner is the Deputy Head of Research & Strategy at LIH’s Department of Infection and Immunity. He is Professor for Immunology & Genetics at the Luxembourg Center for Systems Biomedicine (LCSB) of the University of Luxembourg and Professor of Allergology at the University of Southern Denmark. He received a prestigious ATTRACT Consolidator grant from the Luxembourg National Research Fund (FNR), in 2015 to set up the Experimental & Molecular Immunology research group at LIH. The FNR ATTRACT programme supports the national research institutions by expanding their competences in strategic research areas by attracting outstanding young researchers with high potential to Luxembourg.