“I think it’s pretty early right now, and we would need to find ways to enhance the activity of this enzyme and to do so only in regulatory T cells and not in the rest of the cells,” he says. With PP2A composed of many specific regulatory subunits, a key to any therapy would likely be altering activity at the subunit level, he says.
“By altering the function of a subunit, you can change the function of this enzyme only in this specific cell and not affect its function, its expression, in other cells,” he says. This is a “hot direction” where the lab is now heading, he says. The lab is also developing mouse models that are PP2A deficient in other immune cell subsets.
The finding that PP2A interacts with the mTOR pathway, and in particular decreases the activity of mTORC1, could be particularly useful in clinical application, Dr. Apostolidis says.
“mTOR is a central hub of cellular input integration implicated in metabolism, cell proliferation and cytokine production—it is the focus of intense research in immunology, diabetes, transplant and cancer. By identifying PP2A as an important upstream regulator of mTOR activity, we provided an additional layer of control that can be targeted to modulate mTOR function,” he says. “At the moment, PP2A-targeting drugs are being developed in cancer [research]. Based on our recent work, these drugs can also be used to modify PP2A activity in autoimmune diseases such as SLE, RA, multiple sclerosis and IBD [inflammatory bowel disease].”
He says further studies will be needed to determine whether preferential delivery of PP2A to immune cells is necessary to avoid off-target effects and to maximize the effectiveness on Treg cells.
A more immediate clinical impact of the findings could stem from the observation that ceramides—“the good lipids,” as Dr. Tsokos calls them—are increased in well-functioning Treg cells.
He stopped short of making any specific dietary recommendations, but says, “If you come to think of ways to reconstitute the good lipids, the ceramides, that Tregs need to function well, that will be an advance.”
Thomas R. Collins is a medical writer based in Florida.
References
- Apostolidis SA, Rodriguez-Rodriguez N, Suarez-Fueyo A, et al. Phosphatase PP2A is requisite for the function of regulatory T cells. Nat Immunol. 2016 Mar 14 [Epub ahead of print]
- Sunahori K, Juang YT, Tsokos GC. Methylation status of CpG islands flanking a cAMP response element motif on the protein phosphatase 2Ac alpha promoter determines CREB binding and activity. J Immunol. 2009 Feb 1;182(3):1500–1508.
- Kato H, Perl A. Mechanistic target of rapamycin complex 1 expands Th17 and IL-4+ CD4-CD8- double-negative T cells and contracts regulatory T cells in systemic lupus erythematosus. J Immunol. 2014 May 1;192(9):4134–4144.
