In continuing efforts to prevent, control and cure arthritis, the Arthritis Foundation funds groundbreaking research in a variety of disciplines. In keeping with this mission, the Arthritis Foundation funded the work of Marc Gavin, PhD, while he studied regulatory T cells at the University of Washington in Seattle. Regulatory T cells curtail proinflammatory immune function, so adequate numbers of properly functioning regulatory T cells are necessary to prevent autoimmune reactions in the body – reactions that define several forms of arthritis, including rheumatoid arthritis.

Identifying Immune Suppressor Genes
Dr. Gavin’s Foundation-supported project focused on the role of a gene called Foxp3.  Foxp3 is a transcription factor required for the proper development of regulatory T cells. It controls the activity of other essential regulatory T cell genes, including those that suppress inflammatory reactions.  Dr. Gavin was able to breed mice in which half of the regulatory T cells expressed the Foxp3 gene and half did not express the gene. The team also was able to label these cells so they could be differentiated and studied. The cells that lacked Foxp3 were able to survive and carry out most of their functions, but they could not develop into true regulatory T cells or suppress immune reactions. Scientists can now look at the total gene expression and protein output of these two different cells and determine exactly which genes are involved in immune suppression and how.

Increasing Regulatory T Cell Numbers
One key gene that Foxp3 was found to control directly is phosphodiesterase 3b (PDE3B), which Dr. Gavin was able to identify as a potential therapeutic target. PDE3B is involved in controlling the abundance of cyclic adenosine monophosphate (cAMP), and cAMP is known to suppress T cell function. Because Foxp3 blocks PDE3B expression, regulatory T cells may contain higher amounts of cAMP, which may play an important role in regulatory T cell function. So, Dr. Gavin and colleagues decided to activate the PDE3B gene in regulatory T cells to see what would happen. They found that when the PDE3B protein is produced by regulatory T cells, the total number of regulatory T cells is reduced. They also found that most, but not all, regulatory T cells turn off the PDE3B gene, suggesting that in some cells Foxp3 is not fully functional. If future investigation of human autoimmune disease reveals aberrantly high PDE3B expression in regulatory T cells, then PDE3B inhibitors may be an effective therapy in restoring the regulatory T cell population and its suppression of inflammation.

What Does This Mean to People with Arthritis?
Understanding how individual genes and proteins interact within our immune system opens up doors to scientists who can develop therapies based on that knowledge. In particular, Dr. Gavin and his team learned that suppressing the PDE3B gene can increase the number of regulatory T cells and that the Foxp3 gene is essential for the development of properly functioning regulatory T cells. Now this team of scientists, or others, can take this information and develop therapies to limit the function of PDE3B or bump up the action of other genes that Foxp3 controls.

Gavin MA, Rasmussen JP, Fontenot JD, et al. Foxp3-dependent programme of regulatory T-cell differentiation. Nature 2007; in press.