Novel anti-inflammatory drug target identified by CRISPR
Please can you introduce yourself and tell us what inspired your recent research into how metabolic pathways impact immune function?
I direct the Vanderbilt Center for Immunobiology and have been interested in the field of immunometabolism for more than twenty years. A major focus in this field is to explore metabolic enzymes as potential drug targets to selectively inhibit specific immune cell populations. Our work has focused on the metabolism of T cell subsets in a variety of settings, including inflammatory diseases and cancer.
The metabolic pathway you studied is the one-carbon metabolism. What is a metabolic pathway, and why is the one-carbon metabolism pathway important?
A metabolic pathway is a series of very specific reactions that convert a nutrient into energy and/or building blocks that the body’s cells can use for their daily functions. The one-carbon metabolism pathways are a set of pathways that are required for maintaining the building blocks of DNA and RNA, as well as the markers that regulate the DNA. In our study, we found that these pathways also have signaling roles in T cells that can determine whether the immune response is pro-inflammatory or anti-inflammatory.
In your study, you used CRISPR technology. Why did you choose to use this technology, and how was it applied to your research?
In our study, we used CRISPR technology to screen genes for potential drug targets. We used this approach because of the versatility of this system and its effectiveness compared to earlier approaches. This approach is unbiased and allows us to rapidly assess a long list of genes whether each gene has certain qualities that make a good drug target. CRISPR screening can be applied to many different types of cells and culture conditions. In our study, we used primary T cells and an in vivo lung-inflammation model to identify the most relevant targets for anti-inflammatory therapy.
MTHFD2 was identified as a gene of interest. Can you tell us about this gene and its role in T cell function?
MTHFD2 is an enzyme within the one-carbon metabolism pathways. It is located in the mitochondria and is highly expressed upon T cell activation. It is required for the synthesis of DNA and RNA building blocks. We found that MTHFD2 is critical for T cell proliferation and for promoting the pro-inflammatory function of T cells.
What did you discover about MTHFD2? Were there any particularly surprising findings?
We discovered that blocking MTHFD2 leads to less disease-causing pro-inflammatory T cells and more anti-inflammatory T cells. This was particularly surprising because we were able to alter T cell identity by altering a metabolic pathway. When applied to mouse inflammatory disease models, blocking MTHFD2 led to decreased severity of delayed-type hypersensitivity, multiple sclerosis, and inflammatory bowel disease-associated colitis. In the multiple sclerosis model, in particular, the mice showed significantly fewer symptoms of paralysis, fewer immune cells were invading the spinal cord, and less damage to the protective sheaths surrounding the brain cells.
Overall, what do your findings suggest?
Overall, our findings show that MTHFD2 may be an effective drug target for anti-inflammatory therapy for a wide range of inflammatory and autoimmune diseases. Many of the drugs currently in use can completely suppress the immune system and have many adverse side effects, including susceptibility to infections. Our studies indicate that MTHFD2-targeted therapy may potentially have fewer adverse effects and be effective without being broadly immune suppressive.
Collaboration is of great importance when trying to make new scientific and medical advancements. How important is collaboration in the progress of this research?
Many of our key experiments were performed by our collaborators. Many of our ideas were generated by discussing data with collaborators. Good research is absolutely a collaborative effort. Bringing together many people with diverse expertise and exchanging ideas and skills allows for meaningful progress in research.
How might these findings be applied to treating diseases, such as an inflammatory cancer like colorectal cancer?
In colorectal cancer, inflammation driven by a type of immune cell called Th17 cells is associated with poor survival. Our study specifically found that blocking MTHFD2 not only dampens the activity of Th17 cells but confers anti-inflammatory properties to these cells. Additionally, it promotes the production of a type of anti-inflammatory immune cell called a regulatory T cell.
How has CRISPR screening impacted anti-inflammatory drug target identification, and what role do you see CRISPR having in drug discovery in the future?
CRISPR screening has made it possible to take a systematic and unbiased approach to drug target identification. We can now perform CRISPR screens in specific conditions that better predict a particular gene’s potential performance as a drug target. For example, we performed our screen in an inflammatory disease model to identify an anti-inflammatory drug target. The same paradigm works for many other applications, such as using a cancer model to identify anti-tumor drug targets.
Historically, chemical compounds used as drugs are discovered first, and then their targets are identified. More and more, we are seeing the reverse process, where the drug targets are being identified first, and drugs specific for these targets are being designed. This gives the advantage of having better control of on-target and off-target effects.
What is next for you and your research into the identification of anti-inflammatory gene targets?
We have a wide range of projects ongoing in our lab ranging from studying cancer immunology to inflammatory and autoimmune diseases. The common theme is harnessing the power of cellular metabolic pathways to alter immune cell functions. We are applying the CRISPR screening approach to a variety of projects and hope to identify more effective gene targets for anti-tumor and anti-inflammatory therapy in different types of immune cells.
Where can readers find more information?
About Jeffrey Rathmell, PhD
Dr. Rathmell is the director of the Vanderbilt Center for Immunobiology, associate director of the Vanderbilt Institute for Infection, Immunology and Inflammation, Professor of Pathology, Microbiology and Immunology, and associate director of the Molecular Pathology & Immunology Ph.D. Program at Vanderbilt University Medical Center and Vanderbilt University School of Medicine. He holds the Cornelius Vanderbilt Chair of Immunobiology.
Dr. Rathmell studies mechanisms by which extracellular cues influence lymphocyte death and differentiation in efforts to control inflammatory diseases and leukemia. His group showed that the metabolism of T cells is highly dynamic and that specific metabolic programs are essential for each functional T cell subset. These fundamental metabolic distinctions may now allow modulation of selective populations of lymphocytes in inflammatory diseases and anti-tumor immunity.
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