They began by examining the inability of SLE T cells to produce interleukin 2 (IL‑2), one of the most important cytokines of the immune system. They eventually found that CREB, a transcription factor responsible for the enhancement of IL-2 production, is insufficient in these cells.2
Whey they searched for the causes, they found that SLE T cells have increased PP2A, and that its increase is controlled both genetically and epigenetically and some people are more prone to express more PP2A. They also found that PP2A was central in regulating the activity of other molecules important in regulating T cell function. Researchers then turned to constructing a mouse that overexpresses PP2A only in T cells and found the mouse was highly prone to developing glomerulonephritis.
When they began to look at PP2A in different T cell subsets, they found that regulatory T cells highly express PP2A. They then designed a mouse with regulatory T cells that do not express PP2A.
PP2A in the Crosshairs
Sokratis Apostolidis, MD, the paper’s lead author, who was a research fellow at Beth Israel at the time and is now a resident at the University of Pittsburgh, says the suppression of PP2A had to be handled with great precision.
“PP2A is a highly conserved enzyme from humans all the way to yeast and ubiquitously expressed in the cells of the mammalian body. As a result, and in order to specifically study the role of PP2A in Tregs, we had to generate genetically engineered mice that would lack PP2A activity only in Treg cells. This targeted approach gave us the ability to exclude the effects of PP2A resulting from its deficiency in non-Treg immune cells as well as the rest of the cells of the mice that could confound our findings,” he says.
“The second biggest consideration we needed to take into account was that PP2A is a multi-protein complex and targeting the correct subunit of this complex in Treg cells was crucial. We wanted to cripple the activity of the PP2A enzyme, but at the same time preserve cell viability, because PP2A is involved in the cell cycle as well. That gave us the chance to study live PP2A-deficient Treg cells.”
They found that these mice lacking PP2A in Treg cells developed severe disease.
“This mouse had a lot of inflammation in practically every organ. And continuously it was producing a lot of autoantibodies,” Dr. Tsokos says. These autoantibodies were “practically against everything,” he says, and they included anti-nuclear antibodies, which are common in SLE.
