This was occurring, he says, despite the expression of Foxp3, a transcription factor involved in immune suppression.
“Tregs from this mouse did not have the ability to suppress the function of effector cells—they were expressing Foxp3 but could not function,” he says. “In some ways, we saw that PP2A is there to muscle up Treg cells and if you don’t have PP2A, the cells become emasculated.”
PP2A is known to regulate key cellular processes, such as cell-cycle progression, apoptosis, cellular metabolism & migration, & is involved in the development of cancer & neurodegenerative diseases, as well as SLE.
When looking into the ways PP2A is controlled in regulatory T cells, they found that Treg cells express high amounts of the lipid ceramide—a result of Foxp3 suppressing the production of the enzyme SGMS1, or sphingomyelin synthase 1, Dr. Tsokos says.
This further clarifies the chain of events taking place within regulatory T cells, he says. Without SGMS1, you end up with a lot of ceramide, which activates PP2A, which then inactivates the mTOR signaling pathway, which is responsible for the inflammatory response.
“If you don’t have enough ceramide, you don’t make active PP2A, and the mTOR component of the cell takes over, and it deprives it of its ability to suppress effector cells,” Dr. Tsokos says.
mTORC1 Effects
The researchers’ findings on exactly how PP2A affects the mTOR pathway could be particularly important. They found that when PP2A is activated in Treg cells, there is a distinct effect on the mTORC1 complex, but not on mTORC2. The mTORC1 complex has been shown to promote immunity.
The lab of Andras Perl, MD, PhD, chief of Rheumatology at SUNY Upstate Medical Center, has shown that mTORC1 is increased in SLE T cells compared with those in healthy controls.
When PP2A is activated in Treg cells, there is a distinct effect on the mTORC1 complex, but not on mTORC2. The mTORC1 complex has been shown to promote immunity.
Dr. Perl says the findings from Dr. Tsokos’ lab mark significant progress.
“This is a well-designed study [that] is presented with great precision,” he says. “Due to the clarity of the findings, it is a major step forward.”
He was especially struck by the way the findings dovetailed with findings from his own lab. “My laboratory has uncovered the activation of mTORC1 complex 1 in lupus T cells and we also showed that blockade of mTORC1 with rapamycin or N-acetylcysteine (NAC) provides clinical benefit within the context of clinical trials,” he says. “With direct relevance to this paper, we showed that blockade of mTORC1 by both rapamycin and NAC expanded regulatory T cells in SLE patients in vivo. The current paper suggests that PP2A may act through the very same pathway, and it confirms the importance of mTORC1 in controlling regulatory T cell function in SLE.”
Bottom Line
Developing therapies based on these new findings is likely still far down the road, Dr. Tsokos cautions.
