“Ptpn2 haploinsufficiency increases development of arthritis in mice through an effect on regulatory T (Treg) cells,” says Mattias Svensson, first author of a new study that might account for the association of human autoimmune diseases with loss-of-function single nucleotide polymorphisms (SNPs) in PTPN2 (which encodes the phosphatase PTPN2).

Credit: Springer Nature Limited

Loss of stability of the transcription factor FOXP3 can result in transdifferentiation of FOXP3+ Treg cells into so-called exFOXP3 Treg cells that are pro-inflammatory and contribute to autoimmune disease partly by producing IL-17A.

Although IL-6 was already thought to contribute to the loss of FOXP3 stability, underlying mechanisms were unclear. “We show that PTPN2 is of critical importance in retaining Treg cell stability during autoimmune inflammation,” notes Svensson. “PTPN2 does this by controlling IL-6-induced STAT3 signalling.”

The new data show that severity of disease in two arthritis mouse models that are dependent on innate immune cells (the K/B × N passive serum transfer and collagen antibody-induced models) is not substantially different in Ptpn2+/– mice versus wild-type mice. By contrast, spontaneous or mannan-induced arthritis is exacerbated by haploinsufficiency of Ptpn2 in the T cell-dependent SKG model.

Furthermore, Treg cells transferred into mice (which were then subjected to mannan-induced arthritis) more readily transdifferentiated into exFOXP3 Treg cells if they were sourced from Ptpn2+/– mice, rather than from wild-type mice.

haploinsufficiency in the Treg population is sufficient to modulate disease

Although the severity of disease in the SKG mice might be affected by the level of expression of Ptpn2 by effector T cells or other cell types, fate-mapping data in the new article support that haploinsufficiency in the Treg population is sufficient to modulate disease. Importantly, the researchers also show that in vitro-generated exFOXP3 Treg cells drive de novo arthritis when injected into mice.

“We will continue our studies to further understand the mechanism by which PTPN2 regulates Treg cell stability,” adds Nunzio Bottini, corresponding author of the study. “Hopefully an understanding of this biology might be used in the design of personalized therapies for patients with PTPN2 variants that predispose them to autoimmune diseases.”