“The SPARK program was critical for launching this research direction. And more than that, making connections with SPARK donors has been an unforgettable experience for me. This was a very precious opportunity to see our research through the eyes of donors and the public.”
2024 Tullie and Rickey Families Spark Awards Winner
Kazumasa Suzuki, M.D., Ph.D.
How do regulatory T cells become corrupted to drive autoimmune disease?
Funded: January 2024
Funded by: The generosity of LJI Board Director Barbara Donnell, Bill Passey and Maria Silva, and various donors
Inflammation is a devastating force in autoimmune disease. Inflammation from wayward immune cells damages healthy cells and tissues. Normally, a protein called Foxp3 allows special regulatory T cells (Treg cells) to jump in and suppress this inflammation. When Treg cells lose Foxp3, they can transform into harmful ex-Treg cells. For my SPARK project, I am investigating the role of genetic material called transposable elements (TEs), once considered “junk” DNA, which are now recognized for their roles in inflammation and cancer. I hypothesize that Foxp3 represses TEs in Treg cells. When Foxp3 is lost, TEs increase, leading to inflammation.
I found that Treg cells without Foxp3 convert to ex-Treg cells, which secrete inflammatory substances and have higher levels of TEs. Foxp3 binds near TE sequences on DNA, regulating their expression. My work so far shows that reintroducing Foxp3 has a direct role in suppressing TEs. Targeting ex-Treg cells may prevent Tregs from becoming harmful, which could lead to new autoimmune disease treatments. Going forward, I will test drugs and gene editing to suppress TEs and reduce inflammation—aiming to develop innovative autoimmune disease therapies.
What was the goal of your SPARK project?
Inflammation is a devastating force in autoimmune disease. Normally, a protein called Foxp3 allows Treg cells to jump in and suppress inflammation. Unfortunately, Treg cells sometimes lose Foxp3 and transform into ex-Treg cells, which can drive inflammation. For my SPARK project, I explored why the loss of Foxp3 leads to this Treg cell “corruption.” I investigated the role of genetic material called transposable elements (TEs). TEs were once considered “junk” DNA, but TEs are now recognized for their roles in inflammation and cancer. I used single-cell sequencing and gene editing techniques to test my hypothesis that without Foxp3, TEs increase and Tregs become inflammatory ex-Tregs.
SPARK Project Results
I found that Foxp3 binds near TE sequences on DNA, regulating their expression. I then used gene editing techniques to decrease Foxp3 stability in a mouse model. My experiment showed that loss of Foxp3 pushes Treg cells to spontaneously convert to ex-Treg cells, which secrete inflammatory substances and have higher levels of TEs. We may be able to halt this corruption. My work so far shows that reintroducing Foxp3 has a direct role in suppressing TEs. I believe targeting ex-Treg cells may prevent Tregs from becoming harmful, which could lead to new autoimmune disease treatments.
What’s next for this project?
My next step is to determine exactly how higher levels of TE expression trigger inflammation. Researchers have found that Treg cells have several sensors that can detect TEs, so I will study which TE sensor is linked to pro-inflammatory activity. Once I pinpoint which sensor molecules are most important, I can test new ways to inhibit TE sensing and hopefully block pro-inflammatory signals in Treg cells. Going forward, I will test drugs and gene editing to suppress TEs and reduce inflammation—as I aim to develop innovative autoimmune disease therapies such as systemic lupus erythematosus or rheumatoid arthritis.
What’s next for Kazumasa?
The data and findings from my SPARK project have contributed several review articles and peer-reviewed papers. The experience of presenting my SPARK proposal was also a good opportunity for me to think about how to approach lay people. These accomplishments will be very helpful for me in the next stage of my career. I plan to stay at LJI for several years to continue my research before seeking a position in academia or the biomedical industry.
