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/flLck-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/flFoxp3^YFP-Cre mice). These mice developed dermatitis, splenomegaly, and lymphadenopathy that were much milder than those in Socs1^fl/flLck-Cre⁺ mice. A fate mapping study revealed that Socs1 deficiency accelerated the conversion of Tregs to Foxp3^-IFN-γ⁺ ex-Tregs in the tumor microenvironment and suppressed tumor growth. When transferred into Rag2^-/- mice, Tregs from Socs1^fl/flLck-Cre⁺ mice easily lost Foxp3 expression, whereas those from Socs1^fl/flFoxp3^YFP-Cre mice maintained Foxp3 expression. Although Tregs from Socs1^fl/flLck-Cre⁺ mice produced IFN-γ after a 3-d culture in response to anti-CD3/CD28 Ab stimulation in vitro, Tregs from Socs1^fl/flFoxp3^YFP-Cre mice did not. This finding suggested that the inflammatory conditions in Socs1^fl/flLck-Cre⁺ mice modified the born nature of Socs1-deficient Tregs. To investigate this mechanism, Tregs from Socs1^fl/flFoxp3^YFP-Cre mice were cultured with APCs from Socs1^fl/flLck-Cre⁺ mice. These APCs facilitated STAT4 phosphorylation, IFN-γ production, and loss of Foxp3 expression in Tregs from Socs1^fl/flFoxp3^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.