SOCS1 Is a Key Molecule That Prevents Regulatory T Cell Plasticity under Inflammatory Conditions

We previously showed that regulatory T cells (Tregs) from T cell-specific Socs1-deficient mice (Socs1(fl/fl) Lck-Cre(+) mice) easily convert into Th1- or Th17-like cells (ex-Tregs), which lose Foxp3 expression and suppressive functions in vivo. Because Tregs in Socs1(fl/fl) Lck-Cre(+) mice are constantly exposed to a large amount of inflammatory cytokines produced by non-Tregs in vivo, in this study we analyzed Treg-specific Socs1-deficient mice (Socs1(fl/fl) Foxp3(YFP-Cre) mice). These mice developed dermatitis, splenomegaly, and lymphadenopathy that were much milder than those in Socs1(fl/fl) Lck-Cre(+) mice. A fate mapping study revealed that Socs1 deficiency accelerated the conversion of Tregs to Foxp3(-)IFN-gamma(+) ex-Tregs in the tumor microenvironment and suppressed tumor growth. When transferred into Rag2(-/-) mice, Tregs from Socs1(fl/fl) Lck-Cre(+) mice easily lost Foxp3 expression, whereas those from Socs1(fl/fl) Foxp3(YFP-Cre) mice maintained Foxp3 expression. Although Tregs from Socs1(fl/fl) Lck-Cre(+) mice produced IFN-gamma after a 3-d culture in response to anti-CD3/CD28 Ab stimulation in vitro, Tregs from Socs1(fl/fl) Foxp3(YFP-Cre) mice did not. This finding suggested that the inflammatory conditions in Socs1(fl/fl) Lck-Cre+ mice modified the born nature of Socs1-deficient Tregs. To investigate this mechanism, Tregs from Socs1(fl/fl) Foxp3(YFP-Cre) mice were cultured with APCs from Socs1(fl/fl) Lck-Cre(+) mice. These APCs facilitated STAT4 phosphorylation, IFN-g production, and loss of Foxp3 expression in Tregs from Socs1(fl/fl) Foxp3(YFP-Cre) mice in an IL-12-dependent manner. The results indicate that Socs1-deficient Tregs tend to convert into ex-Tregs under the inflammatory conditions in which APCs are highly activated, and that SOCS1 could be a useful target for enhancement of anti-tumor immunity.